Arquette was living with her family in an artists' commune in Front Royal, VA, when, at age 15, she decided to hitchhike cross-country to San Francisco with three friends. There she worked at Renaissance and Dickens fairs before making her professional stage debut in "Metamorphosis" (1975) at the Story Theater in L.A. 1979 marked both her film debut, a walk-on as a 'Commune Girl' in "More American Graffiti,” and her first stint as a TV regular, playing the teenaged daughter of Shirley Jones on the comedy-drama "Shirley" (NBC, 1979-80). Arquette worked regularly in TV for a period, appearing in after school specials, PBS dramas, and several notable telefilms, notably "The Executioner's Song" (NBC, 1982), for which she received enthusiastic notices as the wild girlfriend of convicted killer Gary Gilmore (Tommy Lee Jones).

Arquette shone in her film lead debut in John Sayles' "Baby, It's You" (1983), portraying a studious Jewish high school student who falls for a rebellious Italian boy (Vincent Spano). She turned in her most memorable performance in Susan Seidelman's comedy "Desperately Seeking Susan" (1985), playing a bored suburban housewife who, after an accident, adopts the freewheeling lifestyle and persona of a woman (Madonna) whom she read about in the personal ads. While this part seemed a perfect springboard to major stardom for the young actress, the major beneficiary of this showcase was actually her co-star Madonna. Later that same year, Arquette was fine as the unstable fatalistic date of Griffin Dunne who acts as the catalyst for the nightmarish events of Martin Scorsese's "After Hours" (1985). Many of her later roles, however, have failed to live up to her early promise.

The pattern for much of Arquette's subsequent Hollywood career would soon be established: leads in small independent films—usually comedies—and foreign features (e.g., "The Big Blue" 1988); female leads in male-oriented action outings (i.e., "Silverado" 1985); and starring roles in films that were barely released or banished straight-to-video (for example, "The Linguini Incident" 1991). There were some bright spots including a co-starring role as a young artist opposite a shambling master painter (Nick Nolte) in Scorsese's "Life Lessons" segment of "New York Stories" (1989) and an outstanding performance as a traveling clairvoyant in Mike Hodges' stylish thriller "Black Rainbow" (1989).

One explanation for Arquette's fall from prominence in the late 80s and early 90s was her decision to live and work in Europe for six years during what could have been her Hollywood prime. She returned to the hurly-burly with an unlikely role opposite action star Jean-Claude Van Damme in "Nowhere to Run" (1993). Arquette was in much better company as part of the high octane ensemble in Quentin Tarantino's acclaimed "Pulp Fiction" (1994), as a tattooed and pierced druggie. She also fared well as Gabrielle, the crippled survivor of an automobile accident who wore her brace like kinky drag, in David Cronenberg's controversial "Crash" and as a robber on the run with a much younger boyfriend in Sondra Locke's little seen "Do Me a Favor" (both 1996). Arquette adopted a more conventional role as an uptight Southerner in "Deceiver" (1999) before returning to her usual offbeat types as a drug addicted blues singer in the low-budget "HK/Hell's Kitchen" (1999). In November 1996, she also made a rare guest appearance as a woman whose life had been touched by violent crime on NBC's "Homicide: Life on the Street” (NBC, 1993-99).

Arquette tried to up her profile with an appearance in “Gone Fishin’” (1997), but the laughably unfunny Joe Pesci-Danny Glover slapstick comedy faired poorly with critics and audiences. After a blip of a role in the Sandra Bullock stinker “Hope Floats” (1998), Arquette returned to the small screen to star in “I Know What You Did” (ABC, 1998) as a tough defense attorney successful at defending rapists who is herself raped by a colleague and blackmailed by a witness after she kills her attacker in self defense. She next starred in “Two Babies: Switched at Birth” (CBS, 199) as a mother who discovers that her child was—wait for it—switched at birth with the baby of another mother (Melissa Gilbert) after a hospital mix-up. After playing the thankless role of unfaithful wife to a veteran police detective in the little-seen cop thriller “Deceiver” (1998), Arquette was engaging as the trampy ex-girlfriend of a recently released convict (Vincent Gallo) in the off-color and amusing “Buffalo ‘66” (1998).

As the millennium drew to a close, Arquette seemed to take just about any role, no matter how big or small, that came her way. After appearing as a Hippie Mother in the historical miniseries “The 60s” (NBC, 1999), she was an actress and former sex symbol distraught over her upcoming job playing Christina Ricci’s mom in Allison Anders’ amusing Sundance comedy, “Sugar Town” (1999). She continued her independent streak, appearing in festival circuit films like “Pigeonholed” (1999), “Palmer’s Pick-Up” (1999) and “I’m Losing You” (1999). Arquette dashed off a couple quick straight-to-video releases, “Voodoo Dawn” (2000) and “Diary of a Sex Addict” (2001) before returning to studio fare with an ho-hum appearance as the wife of a man (Matthew Perry) who befriends a notorious mafia hit-man (Bruce Willis) in “The Whole Nine Yards” (2000). A return to television found the actress playing a cynical magazine editor in “Things Behind the Sun” (Showtime, 2001), a gripping drama about an up-and-coming singer-songwriter (Kim Dickens) struggling with the demons of being gang-raped in high school.

Returning to familiar stomping grounds—indie features—Arquette had a supporting role in “Big Bad Love” (2002), playing the emotionally unsupportive friend of a down-and-out Vietnam veteran (Arliss Howard) desperately trying to turn his turbulent past into fiction. “Big Bad Love” also starred Howard’s wife Debra Winger, which perhaps inspired Arquette to launch her directorial debut with the Showtime documentary “Searching for Debra Winger” (2003), a look at the challenges, pressures and choices female actors face when the reach their 40s and begin to be overlooked for certain roles in favor of their younger counterparts. Winger was a pioneer in the never-ending battle with Hollywood because she bowed out of the business when still in her prime. Following a guest starring two-episode arc in “Will & Grace” (NBC, 1998-2006), Arquette starred as a wife who goes on a rescue mission with a complete stranger (Diego Wallraff) after her husband (Joseph Kell) is kidnapped by a gang of diamond thieves in the Lifetime thriller “Rush of Fear” (2003).