Increasing evidence suggests that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colorectal cancer. This observation is supported by results from animal studies that show fewer tumors per animal and fewer animals with tumors after administration of several different NSAIDs. Results from clinical studies with humans consistently support these findings as well. The intervention data in familial adenomatous polyposis patients establishes that the antineoplastic effect may target human adenoma formation. Supportive evidence comes with both aspirin and non-aspirin NSAIDs. Earlier detection of lesions as a result of drug-induced gastrointestinal bleeding does not seem to account for these findings. The molecular mechanism responsible for the chemopreventive action of this class of drugs is not clear. Protection may affect several pathways, with results including cell cycle arrest, induction of apoptosis, and angiogenesis. This review focuses primarily on the potential chemopreventive activity of NSAIDS in sporadic human colon cancer and adenomas and outlines current concepts for the biologic and biochemical mechanisms for this protective effect.