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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 descendant in the Mafia satire Jane Austen's Mafia (1998).
Because of her injury, Applegate had to wear special shoes to prevent another incident, and in a 2013 interview said that because of what happened, she "actually can't dance anymore.
And that is sad for me because I always wanted to go back.
Applegate followed with roles in films such as Vibrations (1995), Across the Moon (1995), Wild Bill (1995), Tim Burton's Mars Attacks! Applegate was one of the founding members of The Pussycat Dolls, which debuted at Johnny Depp's Viper Room on the Sunset Strip in 1995.
In 1996, Applegate auditioned for the role of Rose in James Cameron's blockbuster hit fim Titanic, but lost to Kate Winslet.
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).
In 2004, she debuted on the Broadway stage playing the title role of Charity Hope Valentine in a revival of the 1966 musical Sweet Charity.
Though the series gained critical praise, it was cancelled in 2000.
The new millennium had Applegate playing the dual role of a 12th-century noblewoman, Princess Rosalind, and her 21st-century descendant, Julia Malfete, in the time-travel comedy Just Visiting (2001).
As an adolescent actress, she started playing the role of Kelly Bundy on the Fox sitcom Married... In her adult years, Applegate established a film and television career, winning an Emmy Award and earning Tony and Golden Globe nominations.
Applegate has had major roles in several films, including Don't Tell Mom the Babysitter's Dead (1991), The Big Hit (1998), The Sweetest Thing (2002), Grand Theft Parsons (2003), Anchorman: The Legend of Ron Burgundy (2004) and its sequel Anchorman 2: The Legend Continues (2013), Hall Pass (2011), Vacation (2015) and Bad Moms (2016).