Hypoglycemia is the limiting factor in the glycemic management of diabetes because it generally precludes maintenance of euglycemia. Improving glycemic control while minimizing hypoglycemia in type 1 diabetes mellitus (T1 DM) involves both application of the principles of aggressive therapy--patient education and empowerment, frequent self monitoring of blood glucose, flexible insulin regimens, individualized glycemic goals and ongoing professional guidance and support--and implementation of hypoglycemia risk reduction. Iatrogenic hypoglycemia is the result of the interplay of therapeutic insulin excess and compromised physiological and behavioral defenses against falling plasma glucose concentrations in T1 DM. Relative or absolute insulin excess occurs when insulin doses are excessive, ill-timed or of the wrong type, when exogenous glucose delivery, endogenous glucose production or insulin clearance are decreased or when insulin-independent glucose utilization or sensitivity to insulin are increased. But these conventional risk factors explain only a minority of episodes of severe hypoglycemia. More potent risk factors include absolute insulin deficiency, a history of severe hypoglycemia and aggressive therapy per se as evidenced by lower glycemic goals, lower hemoglobin A1c levels, or both. These are clinical surrogates of compromised glucose counterregulation, the clinical syndromes of defective glucose counterregulation (the result of absent decrements in insulin and absent increments in glucagon with attenuated increments in epinephrine) and hypoglycemia unawareness (the result of reduced autonomic [sympathochromaffin] activation causing reduced warning symptoms of developing hypoglycemia). The unifying concept of hypoglycemia-associated autonomic failure in T1 DM posits that: (1) Periods of relative or absolute therapeutic insulin excess in the setting of absent glucagon responses lead to episodes of hypoglycemia. (2) These episodes, in turn, cause reduced autonomic (including adrenomedullary) responses to falling glucose concentrations on subsequent occasions. (3) These reduced autonomic responses result in both reduced symptoms of developing hypoglycemia (i.e., hypoglycemia unawareness) and--because epinephrine responses are reduced in the setting of absent glucagon responses--impaired physiological defenses against developing hypoglycemia (i.e., defective glucose counterregulation). Thus a vicious cycle of recurrent hypoglycemia is created and perpetuated. Hypoglycemia risk reduction includes, first, addressing the issue of hypoglycemia--the patient's awareness of and concerns about it, its frequency, severity, timing and clinical settings--in every patient contact. Then it requires application of the principles of aggressive therapy, consideration of both the conventional risk factors and those indicative of compromised glucose counterregulation and appropriate regimen adjustments including a two to three week period of scrupulous avoidance of hypoglycemia in patients with hypoglycemia-associated autonomic failure. With this approach the goals of improving glycemic control and minimizing hypoglycemia are not incompatible.