Chemopreventive strategies for colorectal cancer (CRC) have been extensively studied to prevent the recurrence of adenomas and/or delay their development in the gastrointestinal tract. The non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors have been proven as promising and the most attractive candidates for CRC clinical chemoprevention. The preventive efficacy of these agents is supported by a large number of animal and epidemiological studies which have clearly demonstrated that NSAID consumption prevents adenoma formation and decreases the incidence of, and mortality from CRC. On the basis of these studies, aspirin chemoprevention may be effective in preventing CRC within the general population, while aspirin and celecoxib may be effective in preventing adenomas in patients after polypectomy. Nevertheless, the consumption of NSAID and COX-2 inhibitors is not toxic free. Well-known serious adverse events to the gastrointestinal, renal and cardiovascular systems have been reported. These reports have led to some promising studies related to the use of lower doses and in combination with other chemopreventive agents and shown efficacy. In the intriguing jigsaw puzzle of cancer prevention, we now have a definite positive answer for the basic question if, but several other parts of the equation-proper patient selection, the ultimate drug, optimal dosage and duration are still missing.