Chemoprevention of colorectal cancer involves the long-term use of pharmacologic agents that can prevent neoplasms from developing in the large bowel. This new approach requires major funding and human investments. Among the most widely studied agents for the chemoprevention of colorectal cancer, aspirin, the NSAIDs and COX-2 inhibitors seem to be the most promising. A large number of observational epidemiological studies show that regular use of aspirin and other NSAIDs is associated with a reduction in the risk of developing both colorectal adenomas and cancer. In addition, the prodrug sulindac reduces the growth of existing polyps in familial adenomatous polyposis (FAP). However, the dose, duration of effect and length of protection seen after cessation remain to be fully established. Furthermore, in view of previous discrepancies between the results of observational studies and randomized control trials (RCTs), it is crucially important to investigate the effects of aspirin by RCTs. RCTs investigating the effect of chemopreventive agents on adenoma recurrence as an intermediate endpoint for colorectal cancer is a more feasible approach than RCTs to investigate the effect on the incidence if colorectal cancer per se. Four RCTs of the effect of aspirin on adenoma recurrence are available. Other trials are currently underway.