The concept of hypoglycemia-associated autonomic failure in diabetes posits that in patients with absolute endogenous insulin-deficient diabetes (type 1 diabetes or advanced type 2 diabetes), necessarily imperfect insulin replacement results in falling plasma glucose concentrations, but no decrease in insulin secretion and no increase in glucagon secretion, and, thus, recurrent episodes of hypoglycemia. Those episodes (as well as sleep or prior exercise) attenuate adrenomedullary epinephrine secretion and sympathetic neural activation in response to subsequent hypoglycemia. In the setting of absent insulin and glucagon responses, the attenuated epinephrine responses cause the clinical syndrome of defective glucose counterregulation which is associated with a 25-fold or greater increased risk of severe iatrogenic hypoglycemia during intensive glycemic therapy. The attenuated sympathetic neural responses cause the clinical syndrome of hypoglycemia unawareness, which is associated with at least a sixfold increased risk of severe iatrogenic hypoglycemia during intensive glycemic therapy. The resulting recurrent hypoglycemia further attenuates the sympathoadrenal responses to falling plasma glucose concentrations. The research findings, all in humans, that led to this concept, the current views of its pathogenesis, and a potential approach to its prevention are the topics of this chapter.