Zwigoff first won attention in 1985 for his documentary "Louie Bluie", a portrait of the little-known and highly eccentric blues musician and artist Howard Armstrong. He also directed a feature-length documentary on the history of Hawaiian music, "A Family Named Moe". But it was his near two decade association with R. Crumb that would earn him his greatest notice. Zwigoff had first encountered Crumb in the mid-1970s, when the documentarian joined Crumb's band The Cheap Suit Serenaders and later published some of Crumb's underground comic books. Despite his fame as a somewhat controversial figure, Crumb, noted as the creator of Fritz the Cat, Mr. Natural, and the famous figure with elongated legs and a energized expression bearing the slogan 'Keep on Truckin', might have seemed ripe for an examination as an artist and as the virtual creator of the underground comic movement. Yet, Zwigoff's documentary probed with insight the makings of this eccentric artist by focusing not just on Robert Crumb but his family as well. The audience was introduced to a group of individuals of whom Robert Crumb appeared to be the most conventional. Of particular note in the documentary were scenes between Crumb and his brother Charles, his mentor until Charles slid into the abyss of mental illness in his late teens. Making the conversations more poignant between the two was the knowledge that Charles committed suicide soon after the film was shot. The other Crumb brother, Max, has been jailed for molesting women and has a penchant for sitting on a bed of nails.

As the documentary focused on an artist who pushes the edge of mainstream standards, "Crumb" has much sexual material and received an "R" rating. Some have speculated that this is the reason that despite all its accolades the documentary failed to win over the Academy Awards committee. Nevertheless, "Crumb" was a commercial success and appeared on the Top 10 Films of 1994 lists of numerous critics, both mainstream and esoteric. Zwigoff and Crumb are reportedly collaborating on a screenplay, "The New Girl Friend", for which financing has yet to be obtained.

The helmer, though, turned to fictional features in 2001 with "Ghost World", adapted from Daniel Clowes' comic book about two female teen misfits, played to perfection by Thora Birch and Scarlett Johanssen, and an aging, antisocial pop culture addict (Steve Buscemi) . Critics were quick to praise Zwigoff's visual approach to the material as well as its smart screenplay which the director wrote with Clowes. The members of the Motion Picture Academy were also sufficiently impressed to nominate the film for the Best Adapted Screenplay Academy Award. For his follow-up Zwigoff delivered the deliriously cynical holiday comedy "Bad Santa" (2003) starring Billy Bob Thornton as a dissipated, womanizing con man posing as a department store Santa. The subversive, anti-cheery film, with its R-rated brand of profane humor and its take-no-prisoners attitude, was decidely not for everyone but Zwigoff masterfully delivered both on comedy and pathos, refusing to employ any syrupy sweet sentiment.