Lewis' breakout role as the thumb-sucking nymphet struggling for independence from her warring parents in Martin Scorsese's remake of "Cape Fear" (1991) rescued her from sitcom purgatory and earned her an Academy Award nomination as Best Supporting Actress. Her sensuous scenes with a psychotic killer (played by Robert De Niro) were the sensation of the movie, and Lewis' small, brightly piercing eyes and pouty mouth suggested a waifish but free-spirited and sexually--indeed, sometimes dangerously--provocative young woman questing for answers and emotional fulfillment, shattering any notion that she would ever be sitcom fodder again. She stepped in for Emily Lloyd as the college student who becomes involved with her professor in Woody Allen's "Husbands and Wives" (1992), sympathetically essaying the would-be "other woman" role in a film whose story of a crumbling marriage and the husband's affair with a much younger woman mirrored the Allen-Mia Farrow breakup.
Expanding on her child-woman of "Cape Fear", Lewis began her "psychotic waif" period as Gary Oldman's peroxide blonde moll in Peter Medak's hopped-up contemporary film noir "Romeo Is Bleeding" (1993) and adopted a horrifically hilarious spastic laugh and adolescent gawkiness for that year's "Kalifornia". On the road with homicidal partner Pitt and yuppies David Duchovny and Michelle Forbes, her clueless trailer-park Lolita was a perfect "enabler" for Pitt's serial killer. Back on the road for "Natural Born Killers" (1994), more closely matched in sociopathic tendencies with fellow love-thug Woody Harrelson as they terrorized the Southwest on their killing spree, she captured the frighteningly odd emptiness of her character's moral inattention. Tucked amidst these on-the-edge roles was an atypically sweet, reflective turn with Johnny Depp and Leonardo DiCaprio in the offbeat "What's Eating Gilbert Grape" (also 1993), but a reteaming with DiCaprio in "Basketball Diaries" (1995) returned her to familiar low-life terrain as a scuzzy hooker.
Unfortunately, the fast pace of Lewis' personal life was mimicking her out-of-control onscreen reality, and she could no longer hide her drug addiction by the time "The Evening Star" (1996) required her life-imitating-art portrayal of a substance abuser. Taking an 18-month hiatus from movies, she cleaned herself out with the help of Scientology and returned to pictures in the independent film "Some Girls" (1998), acting for the first time with Giovanni Ribisi. Her next project was Garry Marshall's much more ambitious "The Other Sister" (1999), which starred her opposite Ribisi as a mentally-challenged female coming of age sexually. Though many critics objected to the picture's sitcom-like script, Lewis had chosen it for the compelling parallels between the life of her character (who had spent an extended period in an institution) and her own life as both were reentering the world after an absence. Opinion varied regarding her performance, but no one could deny the risk she took in taking the part or that she was completely honest in its creation.
Lewis was featured in some lighter fare, as a tough New Jersey girl in the 1980s period piece "Hysterical Blindness" (2002), the HBO original movie co-starred Emmy nominee Gena Rowlands and Golden Globe recipient Uma Thurman. She was next seen in the thriller "Enough" (2002), which starred Jennifer Lopez as an abused wife and mother who with the help of Lewis' character tries unsuccessfully to escape her abusive husband (played by Billy Campbell). Thier bootless attempts result in a plot for Lopez to kill her abuser. Then, the following year, Lewis took the turn from serious to comical when she was cast as the girlfriend of Luke Wilson's character in the hilarious feature, "Old School" (2003), a raucous comedy about a trio of thirtysomething buddies who try to recapture their college years by starting their own off-campus fraternity.