Insulin receptors in human tissue undergo marked changes in both their concentration and their affinity for insulin. In general, alterations in receptor affinity are associated with rapidly changing metabolic environments and can occur within hours, whereas alterations in receptor concentration appear to require longer time periods for their induction. The association of a given type of receptor alteration (i.e., change in affinity or concentration) with a given clinical state indicates the presence of distinct modulators of the insulin-receptor interaction. We have presented evidence for 2 specific modulators, i.e., insulin itself and anti-insulin-receptor antibodies. In several clinical states, especially those associated with changes in receptor affinity, receptor alterations are unrelated to either ambient insulin levels or anti-receptor antibodies, suggesting the presence of several as yet unknown mediators of the insulin receptor. The direct metabolic consequences of these receptor events are not well established. In several states, the receptor alteration correlated quite well with the clinical sensitivity of the whole organism to insulin, indirectly implicating the receptor as the major control point for insulin sensitivity. In contrast, specific examples were cited in which receptor events are not consonant with observed biologic responses to insulin, thereby suggesting a predominance of postreceptor processes. Finally, it should be emphasized that the study of hormone receptors and their relationship to disease states is in the formative stage. With new and improved methodology we hope we will be able to investigate the entire pathway of insulin action at its target tissues, from the initial receptor binding to the final biologic effect.