A concise review of the literature that evaluates the risk of colorectal cancer among NSAID users has been presented. Animal studies document a protective effect of NSAIDs in preventing colorectal cancers in carcinogen-induced (AOM) models and in Min mice. NSAIDs are protective in the animal model, even if given 14 weeks after administration of the carcinogen, indicating that these agents must be acting early in the adenoma-to-carcinoma sequence. Treatment of FAP patients with NSAIDs causes regression of adenomas that were already present before initiation of therapy. Many epidemiologic studies have examined the relationship between aspirin use and colorectal cancer. Most show a marked decrease in the relative risk (40% to 50%) of this tumor among continuous aspirin users. The appropriate dose and duration of aspirin treatment needed for optimal results are still unknown. Future work, directed at the molecular basis for the chemoprotective effects of NSAIDs in humans, may reveal strategies for the development of better chemopreventive agents. One effect shared by all NSAIDs is inhibition of cyclooxygenase. Presently, whether inhibition of COX-1 or COX-2 is required for the protective effect of aspirin and other NSAIDs is unclear. The authors and others have demonstrated that COX-2 is up-regulated from 2 to 50 fold in 85% to 90% of colorectal adenocarcinomas, making the COX-2 enzyme a more likely target. The authors have also reported a dramatic increase in COX-2 expression in colon tumors that develop in rats after AOM treatment. Drugs are currently being developed that preferentially inhibit either COX-1 or COX-2. If COX-2 is found to be a relevant target in the prevention of colorectal cancer, these newly developed, selective NSAIDs may play a role in future chemoprevention strategies.