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On the November 25 episode of Raw, Mysterio defeated Randy Orton, Drew McIntyre and Ricochet in a fatal-4 way match to become the #1 contender for the United States Championship, earning him an immediate title match with United States Champion AJ Styles. After The O.C. were sent backstage by the referee for interfering in the match, when the referee was stunned by Styles recoiling from a 619 by Mysterio, The O.C. returned to attack Mysterio, only to be overpowered by Orton, who then helped Mysterio take down Styles with a second 619 and an RKO before subsequently pinning Styles to capture his second US title. At a live event at Madison Square Garden on December 26, Mysterio lost the title to Andrade. He then attempted to win the title back on the first Raw of 2020 on January 6, but due to interference by Zelina Vega, Andrade pinned Mysterio to retain the title. On the April 20 edition of Raw, Mysterio pinned Murphy to qualify for The Money in The Bank ladder match. At the event, Mysterio lost. He and Aleister Black were also "thrown off the roof" of the WWE headquarters by King Corbin. The next night on Raw, Mysterio was savagely attacked by Rollins in a tag team match, where he and Black battled Rollins and Murphy, and won by DQ when Rollins pulled Mysterio off of the ring apron. In the midst of the post match assault, Mysterio's eye was severely injured in storyline when Rollins forced his face onto the steel steps due to his frustration at not being able to defeat Drew McIntyre the previous night. This resulted in speculation that Mysterio would "retire" in June as a result, following weeks of being mocked by Rollins.

"You never say never. [sic] But I am very, very comfortable in the position I’m in with Lucha Underground. I love their schedule, I love their style, I love what they have to offer. I don’t think there will ever be another company that has what Lucha Underground has. It’s very unique, exciting, and fresh—this is really something new".

Rey Mysterio teamed up with Mexican luchadors Fenix and Bandido for the main event of the indy super show All In on September 1, 2018. The trio lost to The Golden Elite team of Kota Ibushi and The Young Bucks (Nick and Matt Jackson).

Rey Mysterio made his New Japan Pro-Wrestling (NJPW) debut on June 9, 2018 as part of NJPW's Dominion 6.9 in Osaka-jo Hall show. Mysterio teamed up with Jushin Thunder Liger and Hiroshi Tanahashi, losing to the Bullet Club team of Cody, Marty Scurll and Adam Page.

On June 3, 2018, Mysterio returned to Lucha Libre AAA Worldwide (AAA) at Verano de Escándalo, competing in a three-way match for the AAA Mega Championship against Rey Wegner and Jeff Jarrett, with Jarrett winning.

On January 28, 2018, at the Royal Rumble, Mysterio was a surprise entrant in the men's Rumble match as part of a one-time deal with WWE. He entered at number 27, eliminating Adam Cole before later being eliminated by Finn Bálor. On April 27, Mysterio participated in the 50-man Royal Rumble match at the Greatest Royal Rumble event. He entered at number 28, eliminating Luke Gallows but was eliminated by Baron Corbin. On June 26, Mysterio was revealed as one of the pre-order bonus character for WWE 2K19. On September 19, it was confirmed Mysterio had signed a two-year contract with WWE.

Mysterio faced fellow WWE alumnus Kurt Angle on March 20, 2016 for the upstart URFight promotion. Mysterio successfully defeated Angle in a two-falls match with assistance from rapper Riff Raff. In January 2017, Mysterio noted in an interview that he may consider opening up his own wrestling school. During the interview, he said: "I just thought I would never have the time. Now being able to make that time – to not have the busy schedule I had with WWE – gives me plenty of time to be a family man. I'm hoping that this time I'm spending with my son will open up that idea again and create a Rey Mysterio Wrestling school". On April 30, 2017, at the WCPW Pro Wrestling World Cup – Mexican Qualifying Round, Mysterio won the Mexico Leg with Penta El Zero M defeating Alberto El Patron in the semi-finals, and defeating longtime rival Juventud Guerrera in the finals. In Round 16, Mysterio lost to the English qualifier Will Ospreay.

During an interview with Title Match Wrestling in December 2016, Mysterio was asked if he would ever return to WWE, Mysterio replied:

During his hiatus, it was reported that Mysterio wanted to leave WWE, but the promotion had extended his contract without his approval. Mysterio did not return to WWE programming, and instead appeared in a video message at AAA's Triplemanía XXII and also visited Lucha Underground. On February 26, 2015, WWE officially announced that Mysterio's WWE contract had expired, ending his nearly 13-year tenure with the company.

On March 3, 2015, five days after being released from WWE, it was announced that Mysterio had agreed to work for Lucha Libre AAA Worldwide for the first time since 1995. He made his in-ring return as part of AAA's 2015 pay-per-view Rey de Reyes ("King of Kings") on March 18, 2015. Mysterio teamed up with Myzteziz (formerly Sin Cara in WWE) to defeat the Los Perros del Mal team of El Hijo del Perro Aguayo and Pentagón Jr., with Mysterio scoring the winning pin. This match is notorious for showing wrestler Perro Aguayo Jr.'s death in the ring following a drop kick from Mysterio. Mysterio delivered a dropkick to Perro's back, causing him to fall to the second rope, setting him up for Mysterio's signature "619" wrestling move, which involve Mysterio running towards the rope, grabbing it, and spinning around 180°, hitting the person on the face with his legs. Mysterio, seeing that something was wrong due to Perro becoming limp, purposely missed. The other wrestlers continued performing while each coming up and checking on Perro. They quickly finished the match after realizing that something serious had happened. The ref, wrestlers, and lockerroom crew came out and took Perro out using a piece of plywood. He was pronounced dead by the doctors later that night. His official death was ruled as cardiac arrest.

On May 24, 2015, Mysterio came together with Myzteziz and El Patrón Alberto to form the "Dream Team" for AAA's Lucha Libre World Cup. The trio eventually won the tournament, defeating Johnny Mundo, Matt Hardy and Mr. Anderson in the finals with Mysterio pinning Mundo for the win. For Triplemanía XXIII, AAA's biggest show of the year, a "dream match" between Mysterio and Myzteziz took place. Both wrestlers teamed during their time in WWE and AAA but had never competed against each other. Mysterio was victorious, forcing Myzteziz to submit to a Fujiwara armbar. After the match, Myzteziz turned rudo and sprayed mist at Mysterio's face and challenged him to a Lucha de Apuestas. In early February 2016, AAA announced that Mysterio had left AAA due to financial issues between Mysterio and AAA. Despite not working directly for AAA, Mysterio Jr. participated in the 2016 Lucha Libre World Cup alongside Dr. Wagner Jr. and Dragon Azteca Jr., known as "Team Mexico International" the trio finished in third place.

Mysterio signed with Lucha Underground on December 12, 2015 and appeared on the second season. On January 10, 2016, Mysterio teamed with Dragon Azteca Jr. and Prince Puma to defeat Ivelisse, Johnny Mundo and Son of Havoc and Fénix, Jack Evans, and PJ Black and Cortez Castro, Joey Ryan and Mr. Cisco in a 4-way Trio Tag Team Elimination Match for the Lucha Underground Trios Championship. Mysterio was the second competitor to enter the second ever Aztec Warfare match and was the final elimination by the eventual winner Matanza. On January 31, 2016, at Ultima Lucha Dos, Rey Mysterio defeated Prince Puma in a singles match. Mysterio defeated Chavo Guerrero Jr. in a Loser Leaves Match. On April 9, 2016 Mysterio was in an Aztec Warfare match where he eliminated Matanza Cueto after Mysterio was eliminated by Johnny Mundo.

On March 20, 2015, Mysterio partnered with Extreme Tiger in a match against the tag team of Perro Aguayo Jr. and Manik. Mysterio scored the winning pin on Manik while all involved were unaware that Aguayo was dead (rather than just knocked out) following a dropkick to Aguayo by Mysterio to the middle rope. Mysterio then attempted the 619 on Aguayo and Manik, but did not connect. Aguayo was rushed to a hospital and doctors attempted to revive him, officially pronouncing him dead at 1:00 AM on March 21.

Mysterio then began a feud with Finlay, an opponent chosen by JBL. The rivalry was marked as "Fight vs. Flight", contrasting the fighting styles of both wrestlers – Finlay's physicality, versus the high-flying Mysterio. After fighting to a "no contest" at No Mercy, followed by a double-disqualification in a number one contender's match for Batista's World Heavyweight Championship on the next SmackDown! he defeated Finlay in a Stretcher match at Cyber Sunday. During this feud, he lost a match to Finlay on the November 9 episode of SmackDown! and was part of the winning team at Survivor Series which consisted of both wrestlers on opposing sides (although Mysterio was second to be eliminated).

After an absence of almost a year, Mysterio returned on the July 16 episode of Raw, saving Zack Ryder from his old rival, Alberto Del Rio. On August 19 at SummerSlam, Mysterio unsuccessfully challenged The Miz for the Intercontinental Championship. During the match, Mysterio suffered a legitimate concussion, rendering him inactive for a week, but he returned to SmackDown on the August 31 episode. On September 16 at Night Of Champions, Mysterio failed again to capture the Intercontinental Championship from The Miz in a fatal four-way match, also involving Cody Rhodes and Sin Cara. The following night on Raw, Mysterio and Sin Cara teamed up to defeat Primo and Epico in a tag team match, after which they were attacked by The Prime Time Players (Darren Young and Titus O'Neil). According to Mysterio, he took the decision to leave WWE when he saw no creative direction about his tag team with Sin Cara. In October, Mysterio and Sin Cara entered a tournament to determine the number one contenders to the WWE Tag Team Championship, defeating Primo and Epico in the first round and the Prime Time Players in the semi-finals. Mysterio and Sin Cara were set to face the team of Cody Rhodes and Damien Sandow on the October 15 episode of Raw, but the match was postponed due to Mysterio legitimately suffering from effects of the stomach flu. The final took place the following week, on October 22, where he and Sin Cara were defeated by Rhodes and Sandow. On November 18 at the Survivor Series pay-per-view, Mysterio and Sin Cara were victorious in a 10-man elimination tag team match alongside Brodus Clay, Justin Gabriel, and Tyson Kidd against Primo, Epico, the Prime Time Players, and Tensai. On December 16 at TLC: Tables, Ladders & Chairs, Mysterio and Sin Cara were defeated by Team Rhodes Scholars (Cody Rhodes and Damien Sandow) in a number one contenders Table match for the WWE Tag Team Championship. Two days later on SmackDown, Mysterio was sidelined with a storyline injury when he and Sin Cara were attacked by The Shield. This was used to write them off television, as Mysterio was taking some time off, and Sin Cara underwent a knee surgery. Mysterio returned on January 27, 2013, at the Royal Rumble, entering the Royal Rumble at number fourteen but was eliminated by Wade Barrett. In March, Mysterio took another leave of absence due to a legitimate knee injury, explained in storyline as an attack by Mark Henry.

After eight months, Mysterio returned at a WWE live event on October 17, 2013, and returned to television as part of the Spanish commentary team at Hell in a Cell. On the November 18 episode of Raw, Mysterio saved CM Punk and Daniel Bryan from an attack by The Wyatt Family and The Real Americans (Jack Swagger and Antonio Cesaro), which led to Mysterio being part of a 10-man elimination tag team match at Survivor Series in which Mysterio's team lost after he was eliminated by sole survivor Roman Reigns. At TLC: Tables, Ladders and Chairs, Mysterio teamed with Big Show to unsuccessfully challenge Cody Rhodes and Goldust for the WWE Tag Team Championship in a fatal four-way match also involving Rybaxel (Ryback and Curtis Axel) and The Real Americans. At the Royal Rumble pay-per-view on January 26, 2014, Mysterio entered the Royal Rumble match at #30, but was eliminated by Seth Rollins. At WrestleMania XXX, Mysterio competed in the André the Giant Memorial Battle royal but was eliminated by Cesaro. He appeared on the April 7 episode of Raw, losing to a returning Bad News Barrett and subsequently decided to take time off to heal a wrist injury.

On April 26, 2012, WWE reported that Mysterio had been suspended for 60 days due to his second violation of the company's Talent Wellness Program policy and that his suspension would expire on June 25.

Five days later on the August 20 episode of SmackDown, Mysterio lost to the debuting Alberto Del Rio by submission. Del Rio, however, continued his attack after the match, sidelining Mysterio for a month, in which time Del Rio would taunt him. The following week a feud was sparked between the two, when Del Rio attacked him following a match with Kane. On the October 8 episode of SmackDown, Mysterio defeated Del Rio, and thus ending his undefeated streak. At Bragging Rights, Mysterio represented Team SmackDown, and despite being attacked by teammate Del Rio, he and Edge managed to defeat the rest of Team Raw, giving Team SmackDown the victory. At Survivor Series, Mysterio led a team to victory over Team Del Rio, and at Tables, Ladders & Chairs, both were part of a fatal four-way match for the World Heavyweight Championship, won by Edge. His feud with Del Rio culminated on the January 7, 2011, episode of SmackDown in a two out of three falls match, which Del Rio won by countout.

In the 2011 WWE Draft, Mysterio was drafted back to Raw. On the May 9 episode of Raw, Mysterio lost a triple threat match to determine the number one contender for the WWE Championship. Following the match, Mysterio was attacked by R-Truth, which led to a match between the two at Over the Limit, which R-Truth won. In May, Mysterio started feuding with CM Punk, with the pair exchanging victories on consecutive episodes of Raw. The feud culminated in a singles match on June 19 at Capitol Punishment, where Punk emerged victorious. On July 17 at Money in the Bank, Mysterio failed to capture the Raw Money in the Bank briefcase, as the match was won by old rival Alberto Del Rio. The following night on Raw, Mysterio took part in a tournament for the vacant WWE Championship and advanced to the finals. On July 25, Mysterio defeated The Miz in the final to win his first WWE Championship, but he lost the title to John Cena later that night. On August 15, Mysterio received a rematch for the WWE Championship against new champion Alberto Del Rio, but lost via submission. Mysterio suffered an injury in late August 2011, and a storyline was put in place to write Mysterio off television, by blaming Alberto Del Rio. Mysterio returned at the Slammy Awards to present the Superstar of the Year Award to CM Punk.

Mysterio returned from his suspension at Hell in a Cell, teaming with former tag team partner Batista to face Jeri-Show (Chris Jericho and Big Show) for the Unified Tag Team Championship. They failed to win the titles, as Mysterio was punched and pinned by Big Show. At Bragging Rights, Mysterio was unsuccessful in winning the World Heavyweight Championship in a Fatal Four-Way match involving Batista, CM Punk, and then-champion The Undertaker. During the match, Mysterio broke up Batista's pin on Undertaker costing him the match and the title. After the match, Batista attacked Mysterio, ending their alliance. Mysterio faced Batista at Survivor Series, where he lost by referee stoppage after Batista performed three Batista Bombs on him. Mysterio lost to Batista again in a street fight on the December 11 episode of SmackDown. A week later Mysterio defeated Batista and was named the number one contender for the World Heavyweight Championship, but his title match against The Undertaker on the December 25 episode of SmackDown ended in a no contest after Batista interfered. On January 1, 2010, Mysterio participated in a Beat the Clock Tournament for a World Heavyweight Championship match at the Royal Rumble. In the tournament, he defeated his former rival Chris Jericho in the quickest time, and prevented Batista from beating it by interfering in his match. This led to a number one contender's match between the duo the following week, which also ended in a no contest following interference from the Undertaker. The following week in a re-match, Mysterio defeated Batista in a Steel Cage match, but failed to win the championship at the Royal Rumble.

Later, John "Bradshaw" Layfield (JBL) accepted Mysterio's challenge for Layfield's Intercontinental Championship at WrestleMania XXV, which Mysterio won in 21 seconds. His win made Mysterio the twenty-first Triple Crown Champion in WWE history. Mysterio was drafted back to the SmackDown brand during the 2009 WWE Draft on the April 13 episode of Raw, in the process making the Intercontinental Championship exclusive to SmackDown for the first time since August 2002. He then began an extended feud with Chris Jericho, successfully defending his title at Judgment Day. At Extreme Rules, Jericho managed to unmask Mysterio and pin him for the Intercontinental Championship; while Mysterio managed to cover his face after being unmasked, Jericho took the opportunity to roll him up and win the title. As a result, Mysterio and Jericho were booked in a Title vs. Mask match at The Bash, in which Mysterio emerged from the acclaimed match victorious after tricking Jericho with a second mask. He then moved into a feud with Dolph Ziggler, defeating him at both Night of Champions and SummerSlam. On August 2, WWE announced that Mysterio would be suspended for 30 days, effective September 2, for violating the company's Wellness Policy. In an interview with Mexican newspaper Record, Mysterio stated that he was suspended for a drug he was using for his knee and arm. Mysterio stated that he had a prescription for the drug, but was unable to produce it in time to prevent his suspension due to being on vacation and doing a promotional tour. On the September 4 episode of SmackDown (taped on September 1), Mysterio lost the Intercontinental Championship to John Morrison.

Mysterio made his return on the June 23, 2008, episode of Raw, as the first wrestler to be drafted in the 2008 WWE Draft from SmackDown to the Raw brand. Mysterio made his Raw in-ring debut on July 7, pinning Santino Marella after a 619. General Manager Mike Adamle announced that John Cena was injured and that Mysterio would replace him in the Championship Scramble at Unforgiven. The next week, Mysterio made his return to Raw after an extended absence by attacking Kane, turning back numerous claims that Kane had "ended his career". Mysterio then made his in-ring return at Unforgiven, competing in the World Heavyweight Championship scramble match, which was won by Chris Jericho. Mysterio put his mask on the line in a singles match at No Mercy, which he won by disqualification after Kane attacked him with a steel chair. He defeated Kane again at Cyber Sunday, this time in a No Holds Barred match, and again at Survivor Series, when the pair were on opposing sides in a five-on-five elimination match. Mysterio participated in the 2009 Royal Rumble match, entering first and spending 49 minutes and 24 seconds in the match, before being eliminated by Big Show. The following night on Raw, he qualified for the Elimination Chamber match for the World Heavyweight Championship at No Way Out, but was eliminated by Edge when the two were the last men in the Chamber match.

Mysterio made his in-ring return at SummerSlam on August 26, 2007, defeating Guerrero, after Guerrero obsessed over Mysterio's return as well as wanting to injure Mysterio again. On the August 31 episode of SmackDown!, Mysterio won a "Championship Competition" to become the number one contender for the World Heavyweight Championship, defeating Batista and Finlay. On the September 7 episode of SmackDown!, Mysterio had an "I Quit" match with Guerrero, which he won after hitting Guerrero's knee with a steel chair repeatedly in a similar manner to which Mysterio had been put out of action, to end the feud. Mysterio then began a feud with The Great Khali, which led to a World Heavyweight Championship match at Unforgiven. The match was later made a Triple Threat match, also involving Batista, who won it.

Mysterio has been a subject of several DVDs during his wrestling career, including Rey Mysterio: 619, a 2003 documentary of Mysterio's career and personal life. WWE also produced Rey Mysterio: The Biggest Little Man, a three disc set featuring Mysterio's best matches that was released on October 23, 2007. He was also featured on the DVD Before They Were Wrestling Stars: Rey Mysterio Jr. in 2007 which featured matches from his time in Mexico. Rey Mysterio: The Life of a Masked Man was issued on July 12, 2011. In the UK, Silver Vision released a Mysterio DVD as part of their Best of WWE collection. This featured his matches from SummerSlam 2005, WrestleMania 22, No Mercy 2006, and SummerSlam 2007. Mysterio was later announced as the pre-order bonus character for the WWE 2K19 videogame to be released on October 5.

On March 19, 2007, Sports Illustrated posted on its website an article in its continuing series investigating a steroid and HGH ring used by a number of professional athletes in several sports. That article mentioned several current and former WWE wrestlers, including Gutierrez who was alleged to have obtained nandrolone and stanozolol. WWE subsequently stated that the allegations preceded the Talent Wellness program WWE launched in February 2006. On August 27, 2009, WWE announced that Gutierrez would receive a 30-day suspension due to a violation of the wellness program. Days later Gutierrez defended himself in a newspaper interview by explaining the drugs as being on a prescription for his knee and arm. While the Wellness Policy allows for prescribed drugs, Gutierrez further contested he had been on a family holiday and subsequently in Europe promoting SummerSlam, giving him only a day to provide the prescription after being notified. On April 26, 2012, WWE suspended Gutierrez for 60 days due to a second violation of their wellness program.

Over the course of his time with the company, he has achieved sustained success, and is a two-time Intercontinental champion, two-time United States Champion, a four-time tag-team champion, a three-time Cruiserweight champion, and a three-time world champion. He is also the winner of the 2006 Royal Rumble and has headlined several major WWE pay-per-view events. He departed the company in 2015 and then wrestled on the independent circuit, before returning to WWE in 2018. Per WWE, Mysterio is one of the most well-known and revered performers of all time.

Mysterio participated in the main event of Survivor Series as part of Team SmackDown! along with Randy Orton, Bobby Lashley, Batista, and John "Bradshaw" Layfield who defeated Team Raw (Shawn Michaels, Kane, Big Show, Carlito, and Chris Masters). After Survivor Series, Mysterio started a feud with Big Show after Mysterio eliminated Big Show at Survivor Series, Mysterio would face Big Show in a match billed as "David vs. Goliath" in a SmackDown! special show, and ended as a "no contest" when Big Show's tag team partner Kane interfered in the match. Mysterio continued to feud with Raw's World Tag Team Champions, and found a tag team partner in World Heavyweight Champion Batista. They were booked to face Raw's Kane and Big Show in a tag match at Armageddon. Before Armageddon, Batista and Mysterio defeated MNM on the December 16 episode of SmackDown! to win the WWE Tag Team Championship in a match they both dedicated to Eddie Guerrero. Now the Tag Team Champions, Mysterio and Batista's match with Big Show and Kane was billed as "Champions vs. Champions." Mysterio and Batista lost the match when Kane pinned Mysterio after a chokeslam. On the December 30 episode of SmackDown!, MNM invoked their rematch clause, defeating Batista and Mysterio after interference from Mark Henry to regain the WWE Tag Team Championship. The following week, Mysterio and Batista received their rematch for the titles in a steel cage match, which they lost after more interference by Henry. On the January 13, 2006, episode of SmackDown!, Mysterio was involved in a 20-man battle royal for the vacant World Heavyweight Championship, but was eliminated by Henry.

Mysterio was the second entrant in the 2006 Royal Rumble match. He won the match and earned a world title shot, last eliminating Randy Orton. He lasted 62 minutes, a Royal Rumble record. Orton urged him to put the title shot at stake in a match at No Way Out. In the weeks preceding No Way Out, Orton made disparaging remarks about Eddie Guerrero. Many fans felt the comments were unwarranted and distasteful in the wake of Guerrero's death in November 2005. Orton won at No Way Out, earning Mysterio's title shot for the World Heavyweight Championship at WrestleMania 22. General Manager Theodore Long re-added Mysterio to the WrestleMania title match however, making it a Triple Threat match between Orton, Mysterio, and then-champion, Kurt Angle. At WrestleMania, Mysterio pinned Orton to become the new World Heavyweight Champion. On the following episode of SmackDown!, Mysterio – who was billed as being an "underdog champion", made his first successful World Heavyweight title defense against Orton. Mysterio went on to retain his title again during a WrestleMania rematch on SmackDown! against Angle three weeks later.

Mysterio is a playable character in numerous video games: WCW vs. nWo: World Tour, WCW/nWo Revenge, WCW Mayhem, WCW Backstage Assault, WCW Nitro, WCW/nWo Thunder, WWE WrestleMania XIX, WWE SmackDown! Here Comes The Pain, WWE Day of Reckoning, WWE SmackDown! vs. Raw, WWE Day of Reckoning 2, WWE SmackDown vs. Raw 2006, WWE SmackDown vs. Raw 2007, WWE SmackDown vs. Raw 2008, WWE SmackDown vs. Raw 2009, WWE SmackDown vs. Raw 2010, WWE Legends of WrestleMania, WWE SmackDown vs. Raw 2011, WWE All Stars, WWE '12, WWE '13, WWE 2K14,WWE 2K15, WWE 2K19 as one of the two pre-order bonuses (the other being Ronda Rousey), and WWE 2K20.

After an unsuccessful attempt at regaining the Cruiserweight Title, Mysterio formed a tag team with Rob Van Dam, and went on to win the Tag Team Championship from Kenzo Suzuki and René Duprée on the December 9 episode of SmackDown!. They successfully defended the title against the former champions at Armageddon, before losing the title to the Basham Brothers on the January 13, 2005, episode of SmackDown! after Van Dam was injured.

The match at WrestleMania was part of a storyline in which Guerrero turned on Mysterio and beat him up after abandoning him during a match against MNM for the Tag Team Championship. Then after a no disqualification match against Chavo, Eddie came out and slammed Mysterio on the steel steps, displaying Eddie's increasing frustration with being unable to defeat Mysterio. Guerrero and Mysterio continued to feud, with Guerrero threatening to reveal a secret he and Mysterio shared involving Mysterio's real life son Dominick, unless Mysterio deferred to Guerrero's authority. Guerrero later revealed that, in the storyline, he was Dominick's biological father. The storyline went that Guerrero knew Mysterio was having trouble starting his own family, so Guerrero left Dominick as a baby with Mysterio and his wife Angie to raise. In subsequent weeks, Guerrero threatened to take custody of Dominick, drawing up custody papers and having his lawyer present them to Mysterio. At SummerSlam, Mysterio defeated Guerrero in a ladder match for the custody of Dominick. Their feud ended when Guerrero gained a victory over Mysterio in a steel cage match. On November 13, 2005, Eddie Guerrero was found dead in his hotel room in Minneapolis, Minnesota. That same day at a WWE "Super Show" where SmackDown! and Raw were both taped, Mysterio gave an emotional speech about Guerrero, and in a show of respect removed his mask (though he put his head down, so no one could see his face). Mysterio went on to defeat Shawn Michaels in an interpromotional match later that night. After the match, Michaels and Mysterio hugged in the ring and Mysterio pointed up to the sky, crying, in memory of Guerrero.

Mysterio, along with rapper Mad One, performed the original version of "Booyaka 619", which Mysterio used as his WWE entrance theme around September 2005. Mysterio also performed a rap song, called "Crossing Borders", which appears on the album WWE Originals and was also used as the official theme song for the 2004 No Way Out pay-per-view.

On the March 6, 2003, episode of SmackDown!, Mysterio defeated Tajiri and Jamie Noble in a Triple Threat match to earn a shot at the WWE Cruiserweight Championship. At WrestleMania XIX, he challenged the champion Matt Hardy for the title, but lost after Shannon Moore interfered. On the May 22 episode of SmackDown!, Mysterio defeated Shannon Moore and Crash Holly in a handicap elimination match to regain the number one contendership for the Cruiserweight title, and he defeated Hardy to win his first Cruiserweight Championship (his first reign in WWE and his first singles championship in the WWE) on the June 5 episode of SmackDown!. Mysterio's reign ended when he lost the title to Tajiri on the September 25 episode of SmackDown!. Three months later, on the January 1, 2004, episode of SmackDown!, Mysterio defeated Tajiri to win his second Cruiserweight Championship. After a successful title defense against Jamie Noble at the Royal Rumble, Mysterio lost the title to Chavo Guerrero at No Way Out in February. At WrestleMania XX, Mysterio took part in a Cruiserweight Open for the title, but Guerrero retained the title. On the June 17 episode of SmackDown!, he defeated Chavo Classic for a record-setting third Cruiserweight Championship reign. He successfully defended the title against Classic's son Chavo Guerrero at The Great American Bash. While Mysterio was Cruiserweight Champion, Spike Dudley turned heel after plowing Mysterio through a table and joined the other Dudleys before winning the Cruiserweight Title from Mysterio on the July 29 episode of SmackDown!. At Survivor Series, he participated in a fatal four-way match for the Cruiserweight Title involving the champion Dudley, Chavo Guerrero, and Billy Kidman. Mysterio lost when Dudley pinned Guerrero to retain.

Upon his return to the USA, he worked in IWA Mid-South, the Xcitement Wrestling Federation and the Heartland Wrestling Association, with the likes of Eddie Guerrero and CM Punk. Mysterio traveled to Puerto Rico for the World Wrestling Council and wrestled Eddie (Primo) Colon over the WWC World Junior Heavyweight Championship in early 2002.

In June 2002, Mysterio signed with World Wrestling Entertainment (WWE), and promos that hyped his debut began airing. The "Jr." was dropped from his name and was billed simply as Rey Mysterio. At the insistence of Vince McMahon, Mysterio agreed to wear his mask again. While this angered lucha libre fans in Mexico as it violated tradition, Mysterio did receive permission from an official lucha libre commission to wear his mask again, as he had not lost his mask in a traditional mask vs. mask match. WWE has normally censored footage of Mysterio being unmasked in WCW for kayfabe-based reasons. However, when WWE Classics on Demand rebroadcast WCW Sin in April 2013, a match featuring Mysterio unmasked was left intact.

Mysterio made his WWE debut on the July 25, 2002, episode of SmackDown! as a fan favorite in a match against Chavo Guerrero, which Mysterio won. He eventually began a feud with Kurt Angle, which culminated in a match at SummerSlam that Angle won after forcing Mysterio to submit to the ankle lock. He later formed a tag team with Edge; the two participated in a tournament for the newly created and SmackDown!-exclusive WWE Tag Team Championship. They lost to Kurt Angle and Chris Benoit in the finals of the tournament at No Mercy; the match was voted Match of the Year by the Wrestling Observer Newsletter. After they failed to win the title, Mysterio and Edge defeated Los Guerreros in a number one contender's match on the October 24 episode of SmackDown! to earn a title shot. Two weeks later on November 7, they defeated Angle and Benoit in a two out of three falls match to win their first Tag Team Championship. They soon lost the tag titles to Los Guerreros in a Triple Threat Elimination match that also involved former champions Angle and Benoit at Survivor Series. Shortly after the loss, Mysterio and Edge disbanded as a tag team.

In WCW, Mysterio helped popularize the high-flying lucha libre wrestling style, which is credited with having also helped kick-start the emergence of cruiserweight wrestling in the United States. He also won a number of championships during his time with the company, including the WCW Cruiserweight Championship and the WCW World Tag Team Championship. After WCW closed in 2001, Mysterio returned to Mexico, briefly wrestling for Consejo Mundial de Lucha Libre (CMLL), before signing with WWE in 2002.

At the beginning of 2001, the Filthy Animals feuded with Team Canada, to whom they lost in a Penalty Box match at Sin. At SuperBrawl Revenge, Mysterio unsuccessfully challenged Chavo Guerrero Jr. for the Cruiserweight Title. Kidman and Mysterio participated in a Cruiserweight tag team tournament for the newly created WCW Cruiserweight Tag Team Championship and advanced to the final round where they ended up losing to Elix Skipper and Kid Romeo. On the final episode of Nitro on March 26, they defeated Skipper and Romeo in a rematch to win the Cruiserweight Tag Team Titles before WCW was sold to the World Wrestling Federation (WWF).

On the October 18 episode of Nitro, Mysterio and Konnan teamed up together to defeat Harlem Heat for the World Tag Team Championship. Mysterio, however, was injured during the match and was sidelined as a result. Billy Kidman substituted for Mysterio and teamed with Konnan during their title defense against Harlem Heat and The First Family, in which the Filthy Animals went on to lose the title back to Harlem Heat. Mysterio returned in early 2000 and remained a steady performer, eventually joining the New Blood faction in early 2000 opposing the Millionaire's Club. On the August 14 episode of Nitro, Mysterio and Juventud defeated The Great Muta and Vampiro to win the World Tag Team Championship. They were stripped of the title after Ernest Miller pinned Disco Inferno with the stipulation that if he pinned Disco, Mysterio and Guerrera would be stripped of the title. The Filthy Animals then feuded with The Natural Born Thrillers in the fall of the year. At Fall Brawl, the Filthy Animals fought the Thrillers to a no contest in an Elimination tag team match. Mysterio reformed his tag team with Kidman and the two challenged for the World Tag Team Championship in a Triangle match at Halloween Havoc, facing the champions Natural Born Thrillers and The Boogie Knights, where the Thrillers retained.

Mysterio appeared in the 2000 film Ready to Rumble along with several other wrestlers.

In 1999, after the two factions of nWo reformed, they demanded that the LWO disband. Mysterio refused to take off his LWO colors and was attacked by the nWo as a result. This led to a match at SuperBrawl IX where Mysterio and tag partner Konnan lost a "Hair vs. Mask match" against Kevin Nash and Scott Hall, forcing Mysterio to remove his mask. After the match, he phoned his uncle to tell him the news. Mysterio has publicly expressed his disappointment over being unmasked:

In mid-1999, Mysterio and Konnan joined Master P's No Limit Soldiers, and began feuding with The West Texas Rednecks. At The Great American Bash, they defeated Rednecks members Curt Hennig and Bobby Duncum Jr. in a tag team match. At Bash at the Beach, they defeated the Rednecks in a four-on-four elimination tag team match when Mysterio pinned Hennig. After Master P's departure from WCW, Mysterio formed a stable with Eddie Guerrero and Billy Kidman known as the Filthy Animals, thus turning heel in the process. This was Mysterio's only heel turn in his career. The three wrestlers soon began a feud with the Dead Pool. The Filthy Animals defeated the Dead Pool in a six-man tag team match at Road Wild and at Fall Brawl. On the August 19 episode of Thunder, Mysterio lost the Cruiserweight Title to Lenny Lane.

On the January 15, 1998, episode of WCW Thunder, Mysterio defeated Juventud to win his third Cruiserweight Championship, but lost it nine days later to Chris Jericho at Souled Out. After the match, Jericho continued the beating by using a toolbox he found at ringside. This storyline was used to cover Mysterio's need for a knee operation that kept him out of the ring for six months. He made his return at Bash at the Beach, where he defeated Jericho for his fourth Cruiserweight championship. The next night, however, the result was overturned and the belt returned to Jericho due to Dean Malenko interfering. Later that year, Eddie Guerrero formed a Mexican stable known as the Latino World Order (LWO) (a spin off of New World Order) that included nearly every luchador in the promotion. Mysterio continually refused to join and feuded with Guerrero and the LWO members, including winning a match against longtime rival and LWO member Psicosis in a match at Road Wild. He was finally forced to join the group after losing a match to Eddie Guerrero. Mysterio's on-and-off tag team partner Billy Kidman joined him during the feud with LWO, wrestling against the LWO despite Mysterio being a part of the group. His alliance with Kidman was formed after Mysterio helped Kidman defeat Juventud for the Cruiserweight Championship at World War 3. Mysterio went up against Kidman for the title at Starrcade but was unsuccessful winning back the title in a triangle match that also involved Juventud. Kidman once again defeated Mysterio for the title at Souled Out in a fatal four-way match that also included Psicosis and Juventud.

In early 1997, he feuded with Prince Iaukea over the WCW World Television Championship. Mysterio was defeated in his title match against Iaukea at SuperBrawl VII after Lord Steven Regal attacked him. Mysterio also lost a championship rematch at Uncensored in March. Mysterio soon began a feud with the New World Order (nWo), which culminated when he lost a Mexican Death match to nWo member Konnan at Road Wild in August. Mysterio then became involved in a feud with his real-life friend and Cruiserweight Champion Eddie Guerrero. He defeated Guerrero in a Title vs. Mask match at Halloween Havoc to win the Cruiserweight Championship for the second time. On the November 10, 1997, episode of Nitro, he lost the title back to Guerrero. They had a rematch at World War 3, which Mysterio also lost.

Gutierrez and his wife Angie have two children: a son Dominic (born April 5, 1997) and a daughter (born August 20, 2001). He has tattoos of his children's names on his right and left biceps, tattoos dedicated to his wife, Angie, and a tattoo with the initials EG for his best friend and fellow wrestler, Eddie Guerrero, who died in 2005. He is a devout Roman Catholic, frequently crossing himself before every match and bearing numerous religious tattoos on his body, most notably a cross on his chest attached to rosaries as well as other crosses and allusions to God.

Mysterio made his World Championship Wrestling (WCW) debut on June 16, 1996, at The Great American Bash, challenging Dean Malenko for the WCW Cruiserweight Championship, which Malenko retained by winning. In July at Bash at the Beach, he defeated longtime rival Psicosis in a number one contender's match to earn another opportunity at the Cruiserweight title. The next night, on the July 8 episode of WCW Monday Nitro, he defeated Malenko to win his first Cruiserweight Championship. He reigned as champion for three months, which included title defenses against the likes of Ultimate Dragon, Malenko, and Super Caló before he lost the title to Malenko at Halloween Havoc. Following his Cruiserweight Championship reign, Mysterio challenged Ultimate Dragon for the J-Crown Championship, but was unsuccessful in his title match at World War 3 in November.

Mysterio signed with Paul Heyman's Extreme Championship Wrestling (ECW) in 1995. He debuted in September at Gangstas Paradise, defeating Psicosis, who was also making his ECW debut. A feud between the two began, which included a two out of three falls match and a Mexican Death match. Mysterio also had a series of matches with ECW-newcomer Juventud Guerrera during the first half of 1996.

Gutiérrez was born and raised in Chula Vista, California, and began his professional wrestling career at age 14 in 1989, prior to debuting for Mexican promotion Asistencia Asesoría y Administración (AAA) in 1992, under the tutelage of his uncle, Rey Misterio. He had a brief stint in Extreme Championship Wrestling (ECW) in 1995, before he signed with World Championship Wrestling (WCW).

Gutiérrez made his debut in Mexico on April 30, 1989, when he was 14 years old. He was trained by his uncle Rey Misterio Sr. and wrestled early on in Mexico where he learned the Lucha Libre high flying style that has been his trademark. He had ring names such as "La Lagartija Verde (The Green Lizard)" and "Colibrí (Humming bird)" before his uncle gave him the name of Rey Misterio Jr. In 1991, Mysterio was awarded "Most Improved Wrestler" in Mexico while wrestling as Colibrí.

Óscar Gutiérrez (born December 11, 1974), better known by his ring name Rey Mysterio, is a Mexican-American professional wrestler currently signed to WWE, where he performs on the Raw brand. According to ESPN, he is "widely regarded as the greatest cruiserweight in pro wrestling history".