The ability of insulin to stimulate glucose disposal varies sixfold to eightfold among apparently healthy individuals. The only way that insulin-resistant persons can prevent the development of type 2 diabetes is by secreting the increased amount of insulin that is necessary to compensate for the resistance to insulin action. The greater the magnitude of muscle and adipose tissue insulin resistance, the more insulin must be secreted to maintain normal or near-normal glucose tolerance. Although compensatory hyperinsulinemia may prevent the development of fasting hyperglycemia in insulin-resistant individuals, the price paid is the untoward physiologic effects of increased circulating insulin concentrations on tissues that retain normal insulin sensitivity. This article focused on the interplay between insulin resistance at the level of the muscle and adipose tissue and normal hepatic insulin sensitivity; this leads to the atherogenic lipoprotein profile that is characteristic of insulin-resistant individuals. It would be inappropriate to minimize the importance of differential insulin sensitivity in the genesis of the changes in lipoprotein metabolism that increase CVD risk in insulin-resistant persons. It would be equally remiss not to emphasize that differential tissue insulin resistance also is necessary to explain why insulin-resistant/hyperinsulinemic individuals are more likely to develop the clinical syndromes (with the exception of type 2 diabetes mellitus) that are listed in Box 1.