Known for his idiosyncratic tastes, and regarded as something of an expert on modern experimental music, he has released albums of jazz, noise and guitar rock music. O'Rourke has collaborated with the likes of Thurston Moore, Derek Bailey, Loren Mazzacane Connors, Nurse With Wound, Fennesz, Organum, Henry Kaiser, Flying Saucer Attack, and most recently mixed Joanna Newsom's album Ys.

He has produced albums by artists as varied as Wilco, Stereolab, Kahimi Karie, Quruli, John Fahey, Smog, Faust, Tony Conrad, Bobby Conn, Beth Orton, Joanna Newsom and U.S. Maple.

He mixed Wilco's very successful Yankee Hotel Foxtrot album, which made many reviewers' top ten lists for 2002, and produced their 2004 album, A Ghost Is Born, for which he won a Grammy for "Best Alternative Album". During the recording of Yankee Hotel Foxtrot, O'Rourke collaborated with Wilco member Jeff Tweedy and pre-Wilco Glenn Kotche, a veteran of the Chicago scene and O'Rourke's own solo albums, under the name Loose Fur. Their self-titled debut was released in 2003 with a follow-up in 2006 entitled Born Again in the USA.

O'Rourke has released a large number of albums and was once a member of Illusion of Safety, Gastr Del Sol and the Red Crayola. From 2000 he played bass guitar and guitar with Sonic Youth; he quit as a full member in 2005 to pursue his interest in filmmaking, but continues to play with them in some of their side projects.