This review explains our current understanding of the syndromes of defective glucose counterregulation and hypoglycemia unawareness in persons with diabetes. The physiologic defenses against hypoglycemia — the glucagon and epinephrine responses — are compromised in most people with type 1 diabetes and in many with advanced type 2 diabetes. In addition to hypoglycemia, exercise and sleep are causes of autonomic failure that must be recognized and require changes in the management of diabetes.