There is mounting evidence from studies on experimental cancer in rodents, interventional studies in patients with familial adenomatous polyposis, and some, but not all, epidemiologic investigations, that suggests a chemopreventive effect of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) against colorectal cancer. In addition, the mechanisms by which these agents modulate tumorigenesis are being elucidated in laboratory experiments. Currently available NSAIDs are unlikely to have an acceptable benefit-to-risk ratio for long-term use in an asymptomatic population. Once the discrete chemopreventive mechanisms are established and the genetic background and risk factor profile of individuals who will benefit from chemoprevention are clarified, a low-dose combination of NSAIDs with different targets may optimize efficacy and minimize toxicity. At present, however, colectomy is still the treatment of choice for patients with familial adenomatous polyposis, and early screening and regular surveillance colonoscopies are the choices for those at risk for hereditary nonpolyposis colorectal cancer. In the average-risk individual, endoscopic screening and surveillance will remain the core of efforts to prevent sporadic colorectal cancer.