Consistent experimental, epidemiologic, and recent randomized controlled trial evidence demonstrates that aspirin lowers the risk of colorectal cancer (CRC). Prior expert bodies have recommended against the routine use of aspirin to prevent CRC in individuals at average risk, particularly in view of potential adverse consequences, including gastrointestinal bleeding. However, such recommendations preceded more recent high quality evidence of the benefit of aspirin for the prevention of not only colorectal cancer, but other cancers as well. This review summarizes this compelling body of evidence supporting the chemopreventive efficacy of aspirin. A broad anti-cancer effect of aspirin coupled with its potential role in the prevention of cardiovascular disease may tip the balance in favor of chronic aspirin use for many patients.