Increasingly out and unabashed about his homosexuality, Arquette got big laughs as the androgynous Boy George-esque musician George opposite Adam Sandler in "The Wedding Singer" (1998) and soon went public as a flamoyant transvestite in his personal life, known for his outrageous outfits and inventive hairstyles. He soon found a steady slate of work playing transvestites, women or androgynous characters in such films as "The Movie Hero" (2003), "Killer Drag Queens On Dope" (2003) and "Lords of Dogtown" (2005), and on television in the Showtime series "Beggars and Choosers" as Larry/Lola in the 1999-2000 season, as well as on his sister-in-law Corteney Cox Arquette's series "Friends" and Howard Stern's "Son of the Beach."
Arquette is also an L.A. area underground cartoonist, his most famous strip being "Nico's Mobile Mole," about his friend, actress Nico Petrakis.