I started doing cartoons when I was about 21. I never thought I would be a cartoonist. It happened behind my back. I was always a painter and drawer.

They met each other while Lynda Barry was an artist-in-residence at the Ragdale Foundation and he was land manager of the Lake Forest Open Lands project in Lake Forest Illinois. She garnered attention with her 1988 illustrated novel The Good Times are Killing Me about an interracial friendship between two young girls which was made into a play. At The Evergreen State College in Olympia Washington Barry met fellow cartoonist Matt Groening.

What It Is (2008) is a graphic novel that is part memoir part collage and part workbook in which Barry instructs her readers in methods to open up their own creativity; it won the comics industry's 2009 Eisner Award for Best Reality-Based Work. Her second illustrated novel Cruddy appeared in 1999.