Noted for combining blackly humorous taboo-laden subject matter with simplified and exaggerated cartoon drawing styles, Brunetti was strongly influenced by Charles M. Schulz and Peanuts.

His best known comic work is his largely autobiographical series Schizo, of which four issues appeared between 1994 and 2006, the first 3 of which have been collected as Misery Loves Comedy.

[4] His early work includes also the strip Misery Loves Comedy which he created for the University of Chicago newspaper The Maroon while a student there.

[5][6] He then edited An Anthology of Graphic Fiction, Cartoons, and True Stories (2006, Yale University Press), which was declared a bestseller by Publishers Weekly in January 2007.

[8] Brunetti's nonfiction book Cartooning: Philosophy and Practice (2011, Yale University Press) won a 2012 Eisner Award.