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Romero ran in the 2019 Tucson mayoral election. She won the Democratic primary in August 2019, defeating state senator Steve Farley and developer Randi Dorman. After winning the mayoral primary, her main general election opponent was Ed Ackerley, who was a longtime Democrat running as an independent in hopes of receiving conservative votes. She defeated Ackerley in the general election. Romero became the first-ever female and first-ever Latina mayor of Tucson, and the first Latino mayor of the city since Estevan Ochoa, who was mayor from 1875 to 1876.

Romero announced her candidacy for reelection in the 2023 Tucson mayoral election on International Women's Day. She promised to serve and represent all Tucson residents, working with other mayoral candidates and equally representing her supporters and those who vote for other candidates. Expressed during her campaign for reelection, Romero wanted to focus on road infrastructure, climate change, public safety, and gun violence. Romero plans to continue using both the city’s general fund and the Highway User Revenue Fund to improve roads. For climate change, she wants to continue using federal funds to transition to lower-emissions buses, continue the goal of planting 1 million trees by 2030, and increase water levels in Lake Mead through reservoir usage. For public safety, Romero wants to continue developing her Community Safety, Health and Wellness Program that was launched in early 2022. Non-law enforcement citizens will respond to non-emergency calls to connect citizens to community organizations and agencies that address homelessness, mental health, substance use, and poverty in Tucson. Lastly, Regina Romero's campaign highlighted the combatting of gun violence through the efforts of the Place Network Investigations strategy. This strategy uses Tucson’s police department in collaboration with businesses, Tucson government departments, and citizens to address crime hotspots and networks.

In the end, facing Republican Janet Wittenbraker, Romero won reelection 61% to 31%.

Regina Romero, a 49-year-old Latina politician, is the youngest of her 6 siblings and descendant of parents who emigrated to Arizona from Mexico. Raised by her farmworker parents in Somerton, Arizona, Romero became the first person in her family to graduate from college and the first to vote. Regina Romero got her BA at University of Arizona and a postgraduate certificate from Harvard University’s School of Government. In addition to being the Mayor of Tucson, Romero is the Chair of the Latino Alliance of the U.S. Conference of Mayors, Co-Chair of Mayors Against Illegal Guns , an inaugural member of the Mayors Alliance to End Childhood Hunger , and a member of the Climate Mayors Network. Regina Romero's family includes her two children and husband, Ruben Reyes.

Regina Romero's political career started with roles as program coordinators in Pima County, Arizona. She began as the coordinator for Pima's youth internship program, serving from 1996 to 2000. From 2000 to 2005, Romero served as Pima's program coordinator for neighborhood reinvestment. Subsequently, from 2005 to 2007, Romero held the position of a council aide for Tucson, Arizona's City Council. Before starting her career as Tucson's first female mayor of Mexican descent, Regina Romero spent 2007 to 2019 as a three-term Tucson City Council member.

During her campaign, she promised to serve and represent all Tucson residents, working with other mayoral candidates and equally representing her supporters and those who vote for other candidates.

As the incumbent candidate, Romero's plan, expressed during her campaign, was to focus on road infrastructure, climate change, public safety, and gun violence. Romero plans to continue using both the city’s general fund and the Highway User Revenue Fund to improve roads. For climate change, she wants to continue using federal funds to transition to lower-emissions buses, continue the goal of planting 1 million trees by 2030, and increase water levels in Lake Mead through reservoir usage.

For public safety, Romero wants to continue developing her Community Safety, Health and Wellness Program that was launched in early 2022. Non-law enforcement citizens will respond to non-emergency calls to connect citizens to community organizations and agencies that address homelessness, mental health, substance use, and poverty in Tucson. Lastly, Regina Romero's campaign highlighted the combatting of gun violence through the efforts of the Place Network Investigations strategy. This strategy uses Tucson’s police department in collaboration with businesses, Tucson government departments, and citizens to address crime hotspots and networks.