Hypoglycemia unawareness--loss of the neurogenic (autonomic) warning symptoms of developing hypoglycemia--is one of three hypoglycemia-associated clinical syndromes that exemplify hypoglycemia-associated autonomic failure in IDDM. Reduced awareness of developing hypoglycemia (an elevated glycemic threshold for symptoms) is a feature not only of hypoglycemia unawareness but also of the syndromes of defective glucose counterregulation, elevated glycemic thresholds for symptoms, and activation of glucose counterregulatory systems during effective intensive therapy. These syndromes are major risk factors for severe iatrogenic hypoglycemia in individuals with IDDM. Their pathogenesis is unknown and likely multifactorial. Recent antecedent iatrogenic hypoglycemia may be one factor, perhaps a major factor, that, by reducing both the symptoms of and defenses against developing hypoglycemia, results in recurrent iatrogenic hypoglycemia, thus creating a vicious cycle. On the other hand, treatment with human compared with animal insulin does not appear to be an important factor.