The authors have presented a concise review of the studies which evaluate the risk of colorectal cancer among NSAID users. Animals studies have clearly documented a protective effect of NSAIDs in preventing colon cancers in a carcinogen-induced (AOM) model. NSAIDs are protective in the animal model, even if given 14 weeks after administration of the carcinogen, indicating that they must be playing a role very early in the adenoma-to-carcinoma sequence of events. Several studies have indicated that treatment of FAP patients with NSAIDs causes a regression of adenomas that were already present prior to initiation of NSAID therapy. Many epidemiological studies have examined the relationship between aspirin use and colorectal cancer. Most of these studies have shown a marked decrease in the relative risk (40-50%) of colorectal cancer among continuous aspirin users. The appropriate dose and duration of aspirin treatment for optimal effects 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 their ability to inhibit cyclooxygenase. Presently, it is not clear whether inhibition of cyclooxygenase-1 or -2 effects on other signaling pathways are required for the protective effect of aspirin and other NSAIDs. The authors and others have demonstrated that COX-2 is upregulated from 2- to 50-fold in 85-90% of colorectal adenocarcinomas, which makes the COX-2 enzyme a possible target. Drugs are currently under development at several pharmaceutical companies that preferentially inhibit either COX-2 or COX-2. If COX-2 is found to be a relevant target in the prevention of colorectal cancer, then these newly developed, more selective NSAIDs may play a role in future chemoprevention strategies.