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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.

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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).

She has also starred in numerous Broadway theatre productions, such as the 2005 revival of the musical Sweet Charity.

Applegate has played the lead role in the television sitcoms Jesse (1998–2000), Samantha Who? and her mother, Nancy Lee Priddy, is a singer and actress.

Her parents were separated shortly after her birth.

She has two half-siblings (Alisa and Kyle) from her father's remarriage.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).In 1986, Applegate won the role of Robin Kennedy (1986–87), a policeman's daughter, in the police drama series Heart of the City.Meanwhile, she was also seen guest starring in several other television series such as All is Forgiven, Still the Beaver, Amazing Stories, and the Family Ties episode "Band on the Run" (1987) as Kitten.After her parents' divorce, her mother had a relationship with musician Stephen Stills.

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