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Murphy landed her first job in Hollywood when she was age 14, starring as Brenda Drexell in the series Drexell's Class. She then went on to play Molly Morgan in the short-lived The Torkelsons spinoff Almost Home. Murphy also guest-starred on several television series including Parker Lewis Can't Lose, Blossom, and Frasier. She also had recurring roles on Sister, Sister; Party of Five; and Boy Meets World. In 1997, she began voicing the character of Luanne Platter (as well as the younger version of Joseph Gribble) on the long-running animated series King of the Hill.

Murphy starred in many successful films, including Clueless (1995); Girl, Interrupted (1999); Drop Dead Gorgeous (1999); Don't Say a Word (2001); the TV adaption of the novel The Devil's Arithmetic (2001); 8 Mile (2002) and Uptown Girls (2003) as well as many lesser-known films, such as Spun (2003). In 2004, she starred in the romantic comedy Little Black Book, and the critically acclaimed Sin City (2005). She starred in two Edward Burns films: Sidewalks of New York (2001) and The Groomsmen (2006). In 2009, she was cast in the Lifetime TV movie, Tribute, as the main character, Cilla. She was set to appear in the Sylvester Stallone film, The Expendables, which will be released in 2010.

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At 8:00 a.m. (16:00 UTC) on December 20, 2009, the Los Angeles Fire Department responded to "a medical request" at the Los Angeles home Murphy and Monjack shared. She apparently collapsed in a bathroom. Firefighters attempted to resuscitate Murphy on the scene, and she was subsequently transported to Cedars-Sinai Medical Center, where she was pronounced dead on arrival at 10:04 a.m. after going into cardiac arrest. Cause of death is yet to be determined, but Assistant Chief Coroner Ed Winter told the Associated Press: "It appears to be natural.

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