The response of plasma glucose and insulin to infusion of glucose and of epinephrine plus propranolol were examined in normal subjects and in two patients with surgically proven insulin-secreting islet cell tumors. The plasma immunoreactive insulin concentration in the two patients was both inappropriate and independent of the plasma glucose concentration. Their insulin secretion was neither increased by physiologic stimulants nor decreased by pharmacologic inhibitors of insulin secretion. There are diagnostic uses for these data as well as theoretical implications. We propose a physiological approach to establish the diagnosis of insulin-secreting islet cell tumors.