Resistance to insulin consists in a decrease in insulin's biologic action and is manifested mainly by hyperinsulinism. Clinical investigation of insulin resistance states relies on specialized tests, performed both in vitro and in vivo. The hyperinsulinemic-euglycemic clamp is the reference method for quantifying insulin resistance and can differentiate decreased insulin sensitivity and decreased maximal capacity for glucose uptake. Glucose flux measurements, using glucose labelled with stable isotopes, distinguish hepatic and peripheral factors involved in insulin resistance. In vitro studies include investigations for antibodies against insulin and insulin receptors, studies of insulin receptors and their tyrosine kinase activity, and studies of postreceptor cell metabolism. These investigations are especially useful in genetic syndromes of extreme insulin resistance, whose pathophysiology is largely unelucidated, including: insulin resistance syndromes with acanthosis nigricans, obesity-acanthosis nigricans-hyperandrogenism syndrome, lipoatrophic diabetes, leprechaunism, and other syndromes. But insulin resistance also plays a major role in non-insulin-dependent diabetes mellitus, insulin-dependent diabetes mellitus, and various pathological or even physiological endocrine alterations.