Arquette was born Robert Arquette in Los Angeles, California to Brenda Olivia "Mardi" (née Nowak), an actor, poet, theater operator, activist, acting teacher, and therapist, and Lewis Arquette, an actor and director. Her paternal grandfather was comedian Cliff Arquette. Her mother was Jewish, the daughter of a Holocaust refugee from Poland. Her father was a convert to Islam from Catholicism, and was related to explorer Meriwether Lewis. Arquette's siblings are actors Rosanna, Patricia, Richmond, and David.
In 1982, at the age of twelve, Arquette's first job was as "this little kid who's on a ride with all these women and whatnot" in the music video "She's a Beauty" by The Tubes. In 1986, Arquette debuted on the big screen in an uncredited role as Alexis, the androgynous friend and bandmate of the sexually ambivalent, angst-filled teenager Max Whiteman (Evan Richards) in the comedy film Down and Out in Beverly Hills. Twenty years later, she transitioned from male to female, an experience that was documented in the film, Alexis Arquette: She's My Brother, which debuted at the 2007 Tribeca Film Festival.
Arquette has appeared in supporting roles in Pulp Fiction as well as mainstream films, including Threesome, Bride of Chucky and an appearance as a Boy George fanatic in The Wedding Singer, performing "Do You Really Want to Hurt Me?". In 2001, Arquette played the Roman emperor Caligula in two episodes of the cult television show Xena: Warrior Princess. That same year, Arquette guest starred in the Friends episode "The One with Chandler's Dad" and had a cameo appearance in Son of the Beach.
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