Hypoglycemia causes substantial morbidity and some mortality in insulin-dependent diabetes mellitus (IDDM). It is often the limiting factor in attempts to achieve euglycemia. The prevention or correction of hypoglycemia normally involves both dissipation of insulin and activation of glucose counterregulatory systems. Among the latter, glucagon plays a primary role initially, whereas epinephrine is not critical, although it becomes critical when glucagon is deficient. Growth hormone and cortisol play demonstrable roles in recovery from prolonged hypoglycemia. Glucose autoregulation may be involved in defense against severe hypoglycemia. With respect to pathophysiology, counterregulatory systems are involved in at least five clinical glucoregulatory syndromes. Defective glucose counterregulation is associated with, and best attributed to, combined deficiencies of the glucagon and epinephrine responses to plasma glucose decrements. Almost assuredly in concert with hypoglycemia unawareness, it results in a markedly increased frequency of severe hypoglycemia, at least during intensive therapy of IDDM. Defined as a night to morning increase in plasma glucose concentration, the dawn phenomenon is thought to result from dissipation of insulin plus the effects of nocturnal growth hormone secretion. Despite a sound rationale, the clinical relevance of the Somogyi phenomenon has been recently questioned. The clinical impression of altered glycemic thresholds for symptoms, i.e., patients with poorly controlled IDDM suffer symptoms of hypoglycemia at relatively high plasma glucose levels, whereas those with very well-controlled IDDM often tolerate subnormal glucose levels, has received experimental support. Clearly, hypoglycemia in IDDM is a problem that needs to be solved. Numerous issues need to be addressed through both basic and clinical research.(ABSTRACT TRUNCATED AT 250 WORDS)