The insulin-receptor interaction is impaired in liver, adipocyte and myocardium plasma membranes of the obese hyperglycemic (ob/ob) mouse. A decreased numer of receptors rather than an altered affinity for the hormone appears to be responsible for this defect. Some studies were conducted with respect to the specificity and the reversibility of the degect. 1) It involves the insulin receptor predominantly if not exclusively. 2) It is largely reversible. a) Fasting ob/ob mice for 40 hr or longer periods improved insulin binding significantly. b) Steptozotocin treatment of ob/ob mice also improved insulin binding in liver membranes. c) In fasting and in streptozotocin-treated mice, glucagon binding exhibited a shift opposite to that of insulin, i.e., it was decreased. These data suggest the possibility that the hormone may "down regulate" its own receptor. Although the mechanism(s) of such regulation, if it is verified, remain(s) to be established, similar observations reported with some other peptide hormones and with catecholamines suggest that this phenomenon may be of general interest in endocrine physiology and patho-physiology.