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Vergara rose to prominence while co-hosting two television shows for Spanish-language television network Univision in the late 1990s. Her first notable acting job in English was in the film Chasing Papi (2003). She subsequently appeared in Four Brothers (2005) and Tyler Perry's comedies Meet the Browns (2008) and Madea Goes to Jail (2009), receiving an ALMA Award nomination for the latter. In 2009, she began playing Gloria Delgado-Pritchett in the ABC comedy series Modern Family for which she was nominated for four Golden Globe Awards, four Primetime Emmy Awards, and eleven Screen Actors Guild Awards.

Vergara has also had roles in the films The Smurfs (2011), New Year's Eve (2011), The Three Stooges (2012), Machete Kills (2013), Fading Gigolo (2013), Chef (2014), and Hot Pursuit (2015). She also had voice-over roles in the animated films Happy Feet Two (2011), Escape from Planet Earth (2013), and The Emoji Movie (2017). Vergara was also the highest-paid Hollywood actress in 2020. Since 2020, Vergara has been a judge on America's Got Talent.