Insulin resistance is a prominent feature of three clinical conditions: obesity, impaired glucose tolerance, and non-insulin-dependent (type II) diabetes mellitus. Numerous studies over the past 15 years have provided a better understanding, from both a clinical and cellular standpoint, of the pathophysiology of these insulin-resistant states as well as of insulin action. In addition, it has recently been recognized that correction of glucose intolerance leads to an improvement in insulin secretion and a reduction in insulin resistance. Examination of the most recent data suggests that the basis for insulin resistance in these common clinical disorders is often multifactorial. In uncomplicated obesity, the cellular alterations responsible for insulin resistance appear to be at the level of the hepatic insulin receptor and in post-binding processes in peripheral target tissues. In type II diabetes, a post-binding defect(s) in peripheral tissues appears to be the primary lesion. In humans, many of the factors that mediate the changes leading to insulin resistance are still unknown and are the object of current investigations.