She debuted in a television movie as young Grace Kelly in the biopic, Grace Kelly (1983) and appeared in her first TV series in Showtime's political comedy, Washingtoon (1985), in which she played a Congressman's daughter.
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 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.
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).
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Her parents were separated shortly after her birth.
She has two half-siblings (Alisa and Kyle) from her father's second marriage.
She was Princess Gwendolyn and Kate in the movie Prince Charming (2001).