Iatrogenic hypoglycemia is a major problem for patients with IDDM. The principles of glucose counterregulation, the physiological mechanisms that normally prevent or correct hypoglycemia, are now known. In concert with decrements in insulin, increments in glucagon, and in the absence of the latter increments in epinephrine, stand high in the hierarchy of redundant glucose counterregulatory factors. In IDDM, iatrogenic hypoglycemia is the result of the interplay of absolute or relative insulin excess and compromised glucose counterregulation. Syndromes of compromised glucose counterregulation include hypoglycemia unawareness (loss of the warning, neurogenic symptoms of developing hypoglycemia), defective glucose counterregulation (the result of combined deficiencies of the glucagon and epinephrine responses to falling glucose levels), and elevated glycemic thresholds (lower glucose levels required) for autonomic activation and symptoms during effective intensive therapy. These have been conceptualized as examples of hypoglycemia-associated autonomic failure. Hypoglycemia unawareness, but not defective glucose counterregulation, is reversible during scrupulous avoidance of iatrogenic hypoglycemia. Clearly, we need to learn to replace insulin in a much more physiological fashion, or to prevent, correct, or compensate for compromised glucose counterregulation, or both, if we are to eliminate hypoglycemia from the lives of people with IDDM without compromising glycemia control. In the meantime we must practice hypoglycemia risk factor reduction with our patients, continue to seek better insight into the fundamental mechanisms of compromised glucose counterregulation, and develop practical preventive clinical strategies.