The relationships between obesity, hyperglycemia, hyperinsulinism and insulin resistance have been studied in mice with congenital obesity (obob). Plasma glucose and insulin of future obese mice were indistinguishable from those of future normal weight mice prior to weaning and the onset of obesity in affected animals. Insulin sensitivity as determined by in vitro uptake of 2-deoxyglucose by intact diaphragm muscle was demonstrable prior to weaning in obob mice. Plasma insulin first rose significantly at age 26 to 32 days, preceding hyperglycemia. By 6 weeks insulin resistance was well developed, as shown by markedly elevated plasma insulin to glucose ratios and poor response of diaphragm muscle to insulin in vitro. Subsequent further rises in plasma insulin paralleled body weight rather than plasma glucose. No abnormalities in diaphragm muscle structure were seen by electron microscopy, suggesting that insulin resistance was not structurally determined. Intravenous and oral glucose tolerances were diabetic by 6 weeks, though oral glucose was capable of producing further 2- to 6-fold increases in plasma insulin compatible with a gastrointestinal component to insulinogenesis. These results suggest that insulin resistance is not likely to be the basic genetic abnormality in obob mice. Hyperinsulinemia and hyperphagia, either causally related or both due to the same genetic hypothalamic disturbance, appear more likely to initiate the obesity seen post weaning. The obesity may then in turn further augment insulin resistance and hyperinsulinism, with diabetes the ultimate outcome. (Endocrinology88: 1230, 1971)