Chemoprevention means the use of agents to prevent, delay, or reverse carcinogenesis. This review was designed to critically discuss the most promising agents in colorectal cancer (CRC) chemoprevention. Aspirin is the best studied chemopreventive agent for CRC. Optimal chemoprevention requires long-term use and high dose of aspirin that may increase the risk of gastrointestinal bleeding. Nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors may also be candidates for chemoprevention. The regular use of nonsteroidal anti-inflammatory drugs, however, causes adverse effects including gastrointestinal bleeding, and cyclooxygenase-2 inhibitors may increase the risk of cardiovascular events. In patients with ulcerative colitis 5-aminosalicylates reduce the risk of CRC and dysplasia. Ursodeoxycholic acid can reduce the risk of dysplasia or CRC in patients with primary sclerosing cholangitis and ulcerative colitis. Current data are insufficient to support the use of hormone replacement therapy to reduce the risk of CRC. Statins may have chemopreventive effects, but further investigation of their overall benefits in preventing CRC is warranted. Antioxidant supplements cannot prevent CRC. The usefulness of selenium, folate, calcium, and vitamin D awaits further evaluation. Chemoprevention cannot yet be accepted as standard medical practice. Use of chemopreventive agents cannot be a substitute for colorectal surveillance.