Colorectal cancer is second to lung cancer as the most common cause of cancer death in the United States; both environmental (diet, physical activity) and genetic (family history, mutations, polymorphisms) factors are related to colon cancer risk. Epidemiologic, animal model, and clinical studies all suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) are potent preventive agents for colon cancer. Most epidemiologic studies (case control, and cohort) are consistent with a protective effect of regular, long-term use of aspirin use, although the prospective Physicians Health Study failed to find a significant protective effect. The entire class of NSAIDs appear to be effective in preventing carcinogen induced colon cancer in animal models. Clinical trials using the NSAID sulindac have shown dramatic regression of colonic adenomas in patients with Familial Polyposis. The biologic and biochemical mechanisms of the putative chemopreventive activity of the NSAIDs is under intense investigation. These drugs can induce cell cycle arrest and apoptosis in colon cancer cell lines through a mechanism that is fundamentally different from the apoptosis caused by cancer chemotherapeutic agents. Sulindac and its metabolites also appear to induce apoptosis in colonic adenomas in vivo. The clinically used NSAIDs are anti-inflammatory due to their ability to decrease prostaglandin synthesis by inhibiting the cyclooxygenase (COX) enzymes. Cyclooxygenase inhibition, particularly COX 2 inhibition, is one putative biochemical target of the chemopreventive activity of NSAIDs. However, recent reports of chemopreventive activity of NSAID derivatives that no longer have COX inhibitory activity suggest that there are other biochemical targets as well.