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In 2019, He appeared in the movie 3pol Trobol: Huli Ka Balbon! as Yorme who was the former Mayor of Balete, Batangas and the leader of the horse ranch.

On May 13, 2019, Domagoso won the mayoralty of Manila, over incumbent Joseph Estrada via a landslide win of close to 150,000 votes more than Estrada. Domagoso was officially proclaimed winner by the City Board of Canvassers the following day, May 14, 2019. Joseph Estrada conceded defeat also on the evening of 13 May.

On July 2017, President Rodrigo Duterte appointed him as the chairman of the board of the North Luzon Railways Corporation (NorthRail) until his resignation in October 2017. In May 2018, he was appointed by Duterte as Undersecretary for Luzon Affairs at the Department of Social Welfare and Development. On October 11, 2018, he officially resigned from his post to run for Mayor of Manila in the 2019 elections.

In 2016, Domagoso announced that he would run for Senator of the Philippines. He lost in his bid, placing 15th overall.

In 2014, he was featured as himself in a Japanese Lifestyle Variety Show, Homecoming in his Vice-mayoralty ruling days. He was a proud godfather of AKB48's half-Filipina half-Japanese member from the 2nd generation, Sayaka Akimoto according to the pictures documented by her Mother. He was interviewed by that show, along with Sayaka and her mom and also Sayaka's co-member Mariko Shinoda and a comedian Hiroshi when they visit Manila.

On February 16, 2013, Domagoso and other five councilors was arrested by the police, due to alleged bingo operations held in a public place, Domagoso denied the bingo game is in a public place in Sta. Cruz, Manila, and he believed that Mayor Lim was involved in his arrest, and the bingo game was not illegal. The day before, Lim and Estrada signed a "Peace Covenant" to prevent any election related violence in the City of Manila.

In May 2012, Joseph Estrada, the former President of the Philippines, announced his intention to run for Mayor of Manila but only for one term in 2013. He ran with Domagoso, who was running for re-election as Vice Mayor. Estrada said, "I’m done with the presidency in Malacañang. Now, I will be moving to the city hall of Manila." He drove his famous “Jeep ni Erap” from San Juan to his new house at Altura, Sta. Mesa, Manila to ceremonially launch his candidacy. He was joined by his wife, former Senator Loi Ejercito and Domagoso. Domagoso said Manileños welcomed Estrada and his wife, adding that they will try to make their stay in Manila comfortable. “We are humbled that the former president of the Philippines will live and stay in Manila,” Domagoso said. “We are thankful he had chosen Manila,” he added.

During his election campaign in 2007, he criticised what he called "black propaganda" by opponents, but did not pursue any charges. Domagoso eventually won the elections, beating the closest rival by about 80,000 votes.

In 2005, during his third term as a councilor of Manila, he returned to acting as a kind-hearted priest in the television drama series Mga Anghel na Walang Langit . He also had a brief appearance in 2007 in the television drama series Bakekang. The following year during his first term as vice mayor, Domagoso had a supporting role in the afternoon soap opera Ligaw na Bulaklak.

Domagoso is married to Diana Lynn Ditan since 2000. They have five children.

Domagoso started his political career when he was elected and sworn as councilor for Manila's first congressional district in 1998 and reelected in 2001 and 2004 respectively. In 2007, he later became vice mayor of the city. He took a crash course in Local Legislation and Local Finance at University of the Philippines Diliman. He then studied public administration in Pamantasan ng Lungsod ng Maynila (University of the City of Manila) while fulfilling his alderman duties.

Domagoso caught the attention of talent scout Wowie Roxas in 1993 while attending a funeral in Tondo and was then persuaded to join show business. He was part of That's Entertainment, a daily variety show featuring German Moreno's stable of aspiring teenage actors, under the screen name Isko Moreno. His major break came in 1993 when he was cast in a cameo role in the romantic movie May Minamahal and became a leading man to Claudine Barretto in Muntik na Kitang Minahal a year later.

Francisco "Isko" Moreno Domagoso (born October 24, 1974), known colloquially as Yorme Isko, is a Filipino politician and former actor who currently serves as the 27th Mayor of Manila since 2019. Prior to becoming mayor, he served as a former three-term councilor of the city's first congressional district from 1998 to 2007 and more recently as the Vice Mayor of Manila from 2007 to 2016. As an actor, Isko Moreno started as a matinee idol and later became known for his mature roles during his short stint in the "titillating films" genre that was prevalent in the country during the 1990s.