Born in Teaneck, New Jersey, Guilfoile was raised in Cooperstown, New York, where his father was an executive at the National Baseball Hall of Fame. Guilfoile graduated from The University of Notre Dame in 1990, and worked briefly in media relations for the Houston Astros baseball club. He was a founding partner of the Chicago design firm Coudal Partners, and a creative director at that company for 11 years. Guilfoile's first novel Cast of Shadows was published by Alfred A. Knopf in 2005. It was named one of the Best Books of 2005 by the Chicago Tribune and Kansas City Star, and has been translated into more than 15 languages.

Guilfoile is a contributor to The Morning News, McSweeney's Quarterly Concern and McSweeney's Internet Tendency. His essays have appeared in The New York Times Magazine, The New Republic, and Salon.com. His work has been anthologized in Mirth of a Nation, 101 Damnations, Chicago Noir, and Chicago Blues.

He is a frequent collaborator with John Warner.