Colorectal cancer is the most common cancer in Western countries and the second leading cause of cancer-related death. Sporadic lesions represent 75-80% of all colorectal cancer, whereas 20-25% are in younger individuals or in patients with a family history of cancer, suggesting a heritable susceptibility. Persons with germline alterations in cancer-promoting genes, such as those with familial adenomatous polyposis and hereditary non-polyposis colorectal cancer, stand to benefit significantly from chemopreventive interventions, along with those who had already developed any colorectal neoplasia (either adenoma or carcinoma). Among the most promising approaches to chemoprevention is the use of non-steroidal anti-inflammatory drugs, including both selective and non-selective cyclooxigenase-2 inhibitors. Although the present article is mainly focused on these drugs and their mechanisms of action, other strategies with potential involvement in colorectal cancer chemoprevention such as peroxisome proliferator activated receptor ligands, epithelial growth factor receptor blockers, calcium, vitamin D, folate, and DNA methyltransferase inhibitors are also reviewed.