The insulin resistance-colon cancer hypothesis, stating that insulin resistance may be associated with the development of colorectal cancer, represents a significant advance in colon cancer, as it emphasizes the potential for this cancer to become a modifiable disease. The fact that the incidence of insulin resistance has been increasing in the United States and much of the rest of the Western world where colon cancer remains the second leading cause of cancer death makes the exploration of the interrelationship of these conditions a subject of high priority. Here, we review the salient features of insulin resistance, defined as impaired biological response to the action of insulin. Recent epidemiological studies, evaluating potential associations between colon cancer risk and diabetes mellitus, dietary intake and metabolic factors, and IGF levels in several clinical settings, provide strong support of the insulin resistance-colon cancer hypothesis (without establishing causality). Mechanistically, insulin resistance has been associated with hyperinsulinemia, increased levels of growth factors including IGF-1, and alterations in NF-kappaB and peroxisome proliferator-activated receptor signaling, which may promote colon cancer through their effects on colonocyte kinetics. It is a reasonable expectation that in the not too distant future, critical interventions to the already mapped molecular sequence of events, which link two apparently disparate entities, combined with lifestyle changes could abrogate the development of colon cancer.