Cancer represents a major challenge for modern medicine. In recent years, chemoprevention, i.e. the administration of a naturally occurring or pharmacological agent to individuals at risk to prevent the development or the recurrence of cancer, has emerged as a realistic option to decrease the morbidity and mortality from colon cancer. There has been intense activity to identify agents, natural or pharmaceutical, which could prevent colon cancer. Epidemiological studies have demonstrated that non-steroidal antiinflammatory drugs reduce by about half the incidence of and mortality from colon cancer. A plethora of preclinical and some clinical studies have further supported this notion. For a chemopreventive agent to be clinically useful, it must be: effective, devoid of significant side effects, inexpensive and convenient to administer. Safety is particularly significance for chemopreventive agents, which will be administered to individuals at risk for many years, if not for the rest of their life. That NSAIDs have a wide spectrum of side effects, some of them life threatening, is a major impediment to their widespread chemopreventive use. Two major recent developments in the search for safer alternatives to NSAIDs include the selective COX-2 inhibitors and nitric oxide-releasing NSAIDs. Given these and other current advances in the field of chemoprevention, we should be optimistic about the eventual eradication of colon cancer.