Objective: To review the prevalence of, risk factors for, and prevention of hypoglycemia from the perspective of the pathophysiologic aspects of glucose counterregulation in diabetes. Methods: This review is based on personal experience and research and the relevant literature. Results: Although it can result from insulin excess alone, iatrogenic hypoglycemia is generally the result of the interplay of therapeutic insulin excess and compromised defenses against declining plasma glucose concentrations. Failure of β-cells of the pancreas-early in patients with type 1 diabetes mellitus but later in those with type 2 diabetes mellitus (T2DM)-causes loss of the first 2 physiologic defenses: a decrease in insulin and an increase in glucagon. Such patients are critically dependent on epinephrine, the third physiologic defense, and neurogenic symptoms that prompt the behavioral defense (carbohydrate ingestion). An attenuated sympathoadrenal response to declining glucose levels-caused by recent antecedent hypoglycemia, prior exercise, or sleep-causes hypoglycemia-associated autonomic failure (HAAF) and thus a vicious cycle of recurrent hypoglycemia. Accordingly, hypoglycemia is infrequent early in T2DM but becomes increasingly more frequent in advanced (absolutely endogenous insulin-deficient) T2DM, and risk factors for HAAF include absolute endogenous insulin deficiency; a history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se. Conclusion: By practicing hypoglycemia risk reduction-addressing the issue, applying the principles of aggressive glycemic therapy, and considering both the conventional risk factors and those indicative of HAAF-it is possible both to improve glycemic control and to minimize the risk of hypoglycemia in many patients.