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At a May 2017 performance, she claimed Daniels, Oprah Winfrey, and Tyler Perry have been blackballing her ever since she did not promote Precious in 2009.

In 2014, Mo'Nique starred in Patrik-Ian Polk's drama film Blackbird as Claire Rousseau.

She concluded, "I've had to sneak and I've had to lie, and I don't want to do that any more. But my husband is so awesome and so fine and so—oh, girl...No other man can compare".

During a 2008 Essence magazine interview, Mo'Nique revealed that she was sexually abused by her brother Gerald from ages 7–11; he went on to sexually abuse another girl and was sentenced to 12 years in prison. After her twin boys were born in 2005, Mo'Nique cut off all contact with Gerald. On April 19, 2010, he admitted on Oprah to sexually abusing her over several years. He also was abused by family members and struggled with substance abuse.

In 2009, she garnered critical acclaim for her performance as the abusive Mary Lee Johnston in the film Precious and won numerous awards, including the Academy Award for Best Supporting Actress. She hosted The Mo'Nique Show, a late-night talk show that premiered in 2009 on BET; it was cancelled in 2011. In 2015, she drew rave reviews for her performance as Ma Rainey in the HBO biopic Bessie and earned a Primetime Emmy Award nomination.

Mo'Nique starred in The Mo'Nique Show, her own late-night talk show. Taped in Atlanta, the show premiered October 5, 2009, on BET.

In 2009, Mo'Nique appeared in the film Precious, directed by Lee Daniels, portraying an inner-city teenager's abusive mother. She won the Sundance Film Festival Special Jury Prize for her performance in the film. The African-American Film Critics Association (AAFCA) awarded Mo'Nique with the Best Supporting Actress Award in December 2009. It also announced that Mo'Nique received the AAFCA's first ever unanimous vote in an acting category. Moreover, she received Best Supporting Actress awards from the Stockholm International Film Festival, the Washington DC Area Film Critics Association, the Los Angeles Film Critics Association, the Boston Society of Film Critics, the New York Film Critics Online, the New York Film Critics Circle, the Southeastern Film Critics Association, the San Francisco Film Critics Circle, the Dallas-Fort Worth Film Critics Association, the Las Vegas Film Critics Society, the Utah Film Critics Association, the Detroit Film Critics Society, the Indiana Film Critics Association, the Online Film Critics Society, the National Society of Film Critics Awards, the Alliance of Women Film Journalists, and the Critics Choice Awards. Time magazine ranked Mo'Nique's outstanding performance as the Best Female Performance of 2009. She won the Academy Award for Best Supporting Actress, the Independent Spirit Award, and the BAFTA Award.

In November 2009, Mo'Nique said, "I own the rights to Hattie McDaniel's life story, and I can't wait to tell that story because that woman was absolutely amazing. She had to stand up to the adversity of black and white [society] at a time when we really weren't accepted. Mr. Lee Daniels is going to direct it, of course, and I'm going to be Miss Hattie McDaniel. I really hope I can do that woman justice."

In 2008, Radio One signed her to her own radio show: Mo'Nique in the Afternoon (or The Mo'Nique Show), which premiered on several Radio One-owned Urban Adult Contemporary-formatted R&B/soul radio stations in July 2008. It mainly aired on these stations that had a local lineup because some Radio One stations did not carry it due to their contracts with Michael Baisden. The show lasted until March 18, 2009, when Mo'Nique decided to leave to "further her career in television, film, and comedy."

Mo'Nique has had a number of supporting roles in film. She appeared in the 2008 comedy film, Welcome Home Roscoe Jenkins with Martin Lawrence. She has had roles in Beerfest, 3 Strikes, Two Can Play That Game, Half Past Dead, and Soul Plane. She voiced a character in Garfield: The Movie, but her role was cut from the movie.

In 2008, Mo'Nique stated on Oprah Winfrey Show that Martin Lawrence gave her invaluable advice about show business: "He pulled me to the side and he said, 'Listen, don't ever let them tell you what you can't have.' Since that day, I've made some of the best deals I've ever made in my career because it keeps ringing in my head...It will stay with me forever."

Mo'Nique's 2007 documentary I Coulda Been Your Cellmate! focuses on incarcerated women. In interviews with individual women, she touches on the common factors that bring many women into the penal system. The documentary was related to her filming a comedy special at the Ohio Reformatory for Women, also known as The Farm. In 2007, Mo'Nique had a guest-starring role on the hit television series Ugly Betty as L'Amanda, Mode's weekend security guard.

Mo'Nique is the author of the best-selling book Skinny Women Are Evil: Notes of a Bigg Girl in a Small-Minded World. She also released a 2006 cookbook called Skinny Cooks Can't Be Trusted.

In 2006, she occasionally filled in for afternoon personality Michael Baisden when his contract with ABC Radio was in the process of getting renewed.

In 2005, Mo'Nique played a significant role in Tony Scott's thriller Domino, co-starring Keira Knightley and Mickey Rourke. In 2006, Mo'Nique was cast as the lead in Phat Girlz, a comedy about an aspiring fashion designer struggling to find love and acceptance. The film was met with lukewarm response from critics and fans. It did earn back its $3 million production cost in its first weekend of release.

Mo'Nique gave birth to twin sons Jonathan and David Hicks in October 2005, two months early. In 2006, she married their father Sidney Hicks. In a New York Times profile, she mentions that she and Hicks have an open marriage:

Mo'Nique hosted the 2003 and 2004 BET Awards and appeared as the host again for the 2007 BET Awards. She received positive responses in July 2004 with her opening performance of Beyoncé's single "Crazy in Love" In 2007, she performed Beyoncé's "Déjà Vu".

Mo'Nique's first play was Eve Ensler's Obie Award-winning production of The Vagina Monologues in March 2002. Mo'Nique, Ella Joyce (Roc); Wendy Raquel Robinson (The Steve Harvey Show and The Game) and Vanessa Bell Calloway (What's Love Got to Do with It), were the first all black celebrity cast to perform The Vagina Monologues. Produced by YYP & Associates, the show was directed by playwright and director Yetta Young as well as co-produced by Kellie R. Griffin, Lisa D. Washington and Anita Cal.

Mo'Nique portrayed Nicole "Nikki" Parker on the UPN television series The Parkers from 1999 to 2004. She was featured on many leading stand-up venues such as Showtime at the Apollo, Russell Simmons' Def Comedy Jam, and Thank God You're Here. Monique tackles race issues in her stand up routines, for instance at the Montreal Just For Laugh Festival in 2000: white and black people, we're just mad at each other, we don't know why we're mad at each other. We're not each other's enemy. We're not the enemy. It's the Chinese people we need to watch out for".

From 1997 to 2001, she was married to Mark Jackson.

Monique Angela Hicks (née Imes; born December 11, 1967), known professionally as Mo'Nique, is an American comedian and Academy Award winning actress. She first gained fame as a member of The Queens of Comedy, as well as her role as Nicole "Nikki" Parker in the UPN series The Parkers while making a name as a stand-up comedian hosting a variety of venues, including Showtime at the Apollo. Mo'Nique transitioned to film with roles in such films as Phat Girlz (2006) and Welcome Home Roscoe Jenkins (2008). In 2002, she, along with several other female comedians, earned a Grammy Award nomination for Best Comedy Album.

Mo'Nique was born on December 11, 1967, in Baltimore, Maryland, the daughter of engineer Alice Imes and drug counselor Steven Imes, Jr. She is the youngest of four children. Mo'Nique graduated from Milford Mill High School in Baltimore County in 1985 and attended Morgan State University. She is a 1987 graduate of the Broadcasting Institute of Maryland.