Sturm became a big fan of comics as a child, starting with Peanuts. While at the University of Wisconsin—Madison, Sturm was pulled back into comics by a chance encounter with a neighbor’s box of underground comics and a copy of Mark Alan Stamaty's Macdoodle Street. In 1988, one year after graduating from UW—Madison, Sturm self-published Down and Out Dawg, a book collecting his college newspaper strips, and Commix, an anthology that featured some of the first works of Chris Ware and Scott Dikkers. In 1990, Sturm was hired as a production assistant on Art Spiegelman’s groundbreaking RAW magazine, and subsequently was published in the second and fourth issues of the Drawn & Quarterly anthology magazine.
1991 was extremely busy for Sturm as he received a Master of Fine Arts from the School of Visual Arts in New York, moved to Seattle and co-founded the alternative newsweekly, The Stranger. Meanwhile, Fantagraphics published his first comic book The Cereal Killings #1. During the next five years James juggled jobs as art director of The Stranger, publisher of his own Bear Bones Press, and work on his own comics, like The Revival, published in 1996. In 1997, Sturm became a professor at the Savannah College of Art and Design, in Savannah, Georgia.
In 1998, Drawn & Quarterly published the story Hundreds of Feet Below Daylight, the second in Sturm's trilogy of American historical fiction pieces. Two years later came the last installment of the trilogy, the best-selling and award-winning graphic novel The Golem's Mighty Swing. This book went on to be printed in three languages, earned praise from such publications as The Sunday Observer, Entertainment Weekly, and The Washington Post Book World, and was chosen as the Best Graphic Novel of 2000 by Time. In 2004, Drawn & Quarterly collected Hundreds of Feet Below Daylight and The Revival as a deluxe comic book titled Above & Below. In October 2007, the trilogy was collected in a volume entitled James Sturm's America: God, Gold, and Golems.
In the 1970s, James saw an interview with Stan Lee on Wonderama, a show on WPIX-TV, and the next day he went out and bought a Fantastic Four Marvel comic book. In 2003, James got the chance to write Unstable Molecules, a four-issue series (later released as a trade paperback) featuring characters based on the Fantastic Four and published by Marvel Comics. Unstable Molecules went on to win an Eisner Award for “Best Limited Series.”
In 2004, Sturm and Michelle Ollie founded the Center for Cartoon Studies, with its first classes offered in the fall of 2005.
In April 7, 2010, Sturm announced he was "quitting the Internet" and, ironically, will write and draw about it for Slate Magazine
Sturm, his wife, and their two daughters live in White River Junction, Vermont.