In the past several decades, research has defined a cluster of metabolic abnormalities with insulin resistance as a major component. Key metabolic disturbances for this syndrome include dyslipidemia (low concentrations of HDL cholesterol, and elevated concentrations of triglycerides, VLDL, and small dense LDL), hypertension, chronic inflammation, procoagulation and impaired fibrinolysis. More recently, an impressive body of epidemiologic data indicates that colon cancer, and possibly some other malignancies, are associated with the insulin resistance syndrome. This evidence includes studies of determinants of the insulin resistance syndrome (obesity, abdominal distribution of adiposity, physical inactivity), metabolic consequences (type 2 diabetes, hypertriglyceridemia, hyperglycemia), and plasma or serum markers (insulin, C-peptide) in relation to colon cancer risk. The mechanism underlying these associations is unknown, but may involve the influence of hyperinsulinemia in enhancing free or bioavailable IGF-1 levels. For other cancers related to obesity, the evidence is suggestive but less firm as that for colon cancer. The role of diet on insulin resistance and hyperinsulinemia is multifactorial; future studies should focus on the comprehensive dietary pattern on insulin resistance and hyperinsulinemia as well as on cancer risk, instead of individual factors. Future studies should also be based on better measurements of insulin resistance, β-cell depletion, and insulin response to assess better which aspects of the insulin resistance are most closely related to cancer risk.