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While appearing in Sweet Charity, Applegate broke her foot, and it was announced that the musical would close during previews.
She persuaded the producers to rescind their decision and on April 18, 2005, she made her Broadway debut.
In 1987, Applegate played the role of the ditzy, sexually promiscuous daughter, Kelly Bundy, on the Fox Network's first sitcom, Married... She portrayed her character for 11 years (1987–97).
While working on the series, Applegate was seen in Dance 'til Dawn (1988, NBC) and in Streets (1990), in which a teenaged drug addict is stalked by a psychotic police officer.
After her television debut with her mother in the soap opera Days of Our Lives and a commercial for Playtex baby bottles at three and five months, respectively, Applegate made her film debut in the 1979 film, Jaws of Satan (or King Cobra) at the age of seven, followed by 1981's Beatlemania.
In 2004, Applegate starred alongside Ben Affleck in the holiday comedy Surviving Christmas, and alongside Matt Dillon in Employee of the Month.
Behind the screen, she was the executive producer of Comforters, Miserable (2001).
Applegate guest-starred in 21 Jump Street (1988) and Top of the Heap (1991, as Kelly Bundy), and hosted Saturday Night Live (May 8, 1993, and October 13, 2012) and MADtv (1996).
The character of Sue Ellen Crandell in the black comedy feature Don't Tell Mom the Babysitter's Dead (1991) was Applegate's first starring role in a mainstream film, playing a rebellious teenager who is forced to take care of siblings after their summer babysitter dies. with Children was cancelled in May 1997, Applegate starred as Claudine Van Doozen in the independent feature Claudine's Return (or Kiss of Fire), was cast in the action-comedy The Big Hit, and played the fiancée of a mob boss in the Mafia satire Jane Austen's Mafia (1998).
In 1998, Applegate was given the title role in the NBC sitcom Jesse.