Ware's earliest strips were published in The Daily Texan, the student newspaper of the University of Texas at Austin. His work attracted the attention of comics legend Art Spiegelman, who invited Ware to contribute to the publication RAW. From there, Ware developed a relationship with Fantagraphic Books, which published one of his most well-known series Acme Novelty Library and the resulting graphic novel Jimmy Corrigan, the Smartest Kid on Earth.

Ware is also known for his non-comics work, designing posters for ragtime performers and bands, the radio program This American Life and films like The Savages.

1. I try to use the rules of typography to govern the way that I "draw", which keeps me at a sensible distance from the story as well as being a visual analog to the way we remember and conceptualize the world. I figured out this way of working by learning from and looking at artists I admired and whom I thought came closest to getting at what seemed to me to be the "essence" of comics, which is fundamentally the weird process of reading pictures, not just looking at them. - Chris Ware, On Cartooning