Preventive medicine is becoming a cornerstone in our concept of health. This is especially significant in regard to cancer, as cancer is predicted to become the leading cause of death, surpassing heart disease, by the end of this decade. The prevention of colorectal cancer (CRC) has become an important public health goal because of the high incidence of CRC, with more than 945,000 new cases expected worldwide in 2006, and the considerable mortality and morbidity associated, with more than 492,000 deaths expected worldwide in the same year. The past 2 decades have seen the emergence of chemopreventive agents that have 1 of 3 effects: inhibiting, delaying, or reversing carcinogenesis. Notwithstanding a substantial body of evidence suggesting an inverse relationship between aspirin or nonsteroidal anti-inflammatory drug use and CRC incidence and mortality, the use of traditional nonsteroidal anti-inflammatory drugs in the chemoprevention of CRC is limited by their gastrointestinal toxicity. The favorable gastrointestinal safety profile of selective cyclooxygenase-2 inhibitors has therefore made them particularly attractive for this purpose. There has been concern, however, that selective cyclooxygenase-2 inhibitors may increase the risk of cardiovascular events, possibly by reducing endothelial prostacyclin production while leaving platelet thromboxane A2 generation unopposed. 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, ultimate drug, optimal dosage, and duration) are missing. The most challenging task is to find the proper place for these interventions in the entire effort of cancer prevention, in subjects at risk for colorectal neoplasia, and in those at risk for other tumors. The achievement of this important goal may contribute to the conversion of CRC into a truly preventable disease.