Down regulation of the insulin receptor of primary cultures of rat hepatocytes occurs in the presence of insulin and several agents with insulin-like activity, which act through or distal to the insulin receptor. These findings indicate that the interaction of insulin with its specific binding site is not in itself sufficient to down-regulate this receptor and that one or more steps subsequent to this interaction are necessary. Thus, down regulation may be a complex biological response to insulin, and if a cell were resistant to this effect of insulin, our data may explain how target cells from a patient or animal can have a normal number of receptors in the presence of increased concentrations of circulating insulin.