The interaction of insulin with its receptor represents one of the key intermediate steps between secretion of insulin and its final biologic effects. Alterations in this interaction have been found in a number of disease states, including obesity, non-insulin-dependent diabetes mellitus (NIDDM), glucocorticoid excess, and acromegaly, as well as several rare forms of severe insulin resistance. The major factor regulating the receptor in obesity and NIDDM appears to be insulin. In obesity this alteration in normal regulation occurs secondary to overeating, whereas in the diabetic state the nature of the primary defect is uncertain. The role of the receptor in insulin resistance and methods for its evaluation are discussed.