Insulin resistance is a major component of non-insulin-dependent diabetes mellitus (NIDDM). While a genetic contribution is likely, as yet none of several proposed candidate genes have been incriminated in the typically obese patient with NIDDM to explain their insulin resistance. Accordingly, this review focuses on some recent advances in understanding three acquired factors contributing to insulin resistance: visceral obesity, glucotoxicity and lipotoxicity. Newer computerized tomography scans allow quantitation of fat accumulating in visceral organs including the mesentery and omentum. This visceral fat relates much more to the insulin resistance syndrome than does subcutaneous fat. Moreover, exercise, as performed by active Sumo wrestlers, is associated with low visceral fat, absent hyperglycemia and absent dyslipidemia despite massive subcutaneous obesity. It remains to be seen whether exercise programs more moderate than Sumo wrestling will also mobilize visceral fat. A new metabolic pathway has recently been described whereby hexosamines are formed by an increased flux of glucose into fat and muscle. These hexosamine products appear to explain how glucotoxicity results in insulin resistance. They act as a negative feedback system to limit further glucose transport by insulin target tissue during hyperglycemia. Lipotoxicity has previously been implicated in insulin resistance by its inhibitory effect on glucose uptake by muscle because of the Randle-fatty acid cycle. Recently the role of elevated fatty acids in producing "hepatic" resistance to insulin in NIDDM has also been documented, but the site of insulin resistance may be the fat cell rather than the hepatocyte. Therapy consists mainly of hygienic measures, including caloric restriction and exercise, which can reverse all three of these acquired forms of insulin resistance. In addition, pharmacologic measures to reduce hyperglycemia can reduce the glucotoxicity and lipotoxicity. The use of insulin-sparing antihyperglycemia drugs may be particularly useful in the insulin-resistant patient to avoid weight gain while correcting the hyperglycemia.