Insulin is the key hormone responsible for regulating the level of glucose in plasma. In several disease states (e.g., obesity, non-insulin-dependent diabetes mellitus, and acromegaly), the target cells are resistant to insulin action. The intramural research program of the NIDDK has a long history of studying patients with rare disorders of extreme insulin resistance. We use what is learned from these rare patients both to develop therapeutics for rare diseases, and to apply what is learned to understand more common forms of insulin resistance.