[4] Over his career, which started in the underground comix era, Griffith has worked with the industry's leading underground/alternative publishers, including Print Mint, Last Gasp, Rip Off Press, Kitchen Sink, and Fantagraphics Books.

[10][11] For a short period in the late 1960s, Griffith joined a team of artists that included Kim Deitch, Drew Friedman, Jay Lynch, Norman Saunders, Art Spiegelman, Bhob Stewart and Tom Sutton,[12] who designed Wacky Packages trading cards for the Topps Company.

[13] He quickly gained a reputation for his willingness to collaborate and organize: one of his first acts upon arriving in San Francisco was to help form the United Cartoon Workers of America,[14] along with Robert Crumb, Justin Green, Art Spiegelman, Spain Rodriguez, Roger Brand, Michele Brand, and Griffith's sister Nancy.

Young Lust, an "X-rated parody of girl's romance comics"[16] that Griffith co-founded and edited with cartoonist Jay Kinney, was a huge hit upon its 1970 debut,[17] with the first issue enjoying multiple printings.

In 1973, Griffith was one of the founding members of Cartoonists' Co-op Press, along with Kim Deitch, Jerry Lane, Jay Lynch, Willy Murphy, Diane Noomin, and Spiegelman.

[21] (For example, Griffith's popular anthology, Young Lust, ran through three publishers — Company & Sons, Print Mint, and Last Gasp — in its first three issues.)

Griffith's solo title, Tales of Toad, had a three-issue run from 1970 to 1973, published first by the Print Mint and then Cartoonists' Co-op Press.

In 1975, after many years of gestation,[25] Griffith and Spiegelman debuted the magazine-sized anthology Arcade, the Comics Revue, published by the Print Mint.

Arriving late in the underground era, Arcade stood out from similar publications by having an ambitious editorial plan, in which Spiegelman and Griffith attempted to show how comics connected to the broader realms of artistic and literary culture.

Soon after the magazine's debut, however, co-editor Spiegelman moved back to his original home of New York City,[29] which put most of the editorial work for Arcade on the shoulders of Griffith and his new partner (later wife), Diane Noomin.

This, combined with distribution problems, retailer indifference, and a general failure to find a devoted audience,[27] led to the magazine's 1976 demise after seven issues.

Nonetheless, many observers credit Arcade with paving the way for the Spiegelman-edited anthology Raw, the flagship publication of the 1980s alternative comics movement.

Their relationship seemed to make Zippy's random nuttiness more directed and Griffy's cranky, critical persona had his foil, someone to bounce happily off of his constant analysis of everything and everyone around him.

[36] In 1986, the "Zippy Theme Song" was composed and performed, with lyrics by The B-52s' Fred Schneider and vocals by The Manhattan Transfer's Janis Siegel.

"[39] In October 1994 Griffith toured Cuba for two weeks, during a period of mass exodus, as thousands of Cubans took advantage of President Fidel Castro's decision to permit emigration for a limited time.

Griffith revealed in the August 19, 2020, Zippy strip that he was writing and drawing a graphic biography of Nancy cartoonist Ernie Bushmiller.