Since 1911, blood sugars have been measured in newborn infants. Significant neonatal hypoglycemia was first reported in 1937. In 1959, the report of transient symptomatic neonatal hypoglycemia generated worldwide reports. This, along with the ongoing advances in studies of energy metabolism, thermal control and oxygen requirements, led to the first conference on Energy and Carbohydrate Metabolism in the newborn in Tokyo, 1965. Subsequently, a number of hypoglycemia syndromes were discovered. Concurrently, pre-, peri- and neonatal care changed dramatically with the survival or very tiny and very sick newborns. These advances in care made previously derived statistical definitions of hypoglycemia irrelevant. New functional definitions are needed to define abnormal glucose concentrations. Significant hypoglycemia is a continuum of low glucose concentrations of varied duration and severity. Its impact depends upon other risk factors as well. In addition, new hypoglycemic syndromes have appeared. These include deficiencies of blood-brain glucose transporters, the association of hyperinsulinemic hypoglycemia with isoimmune thrombocytopenia and a variety of acyl CoA dehydrogenase deficiencies. Concurrently, carbohydrate disorders in infancy appear to be changing. Neonatal diabetes mellitus, previously transient and benign, now shows a high frequency of recurrence and remaining as a permanent condition. Idiopathic ketotic hypoglycemia of infancy has disappeared in the USA. Familial hyperinsulinemic hypoglycemic syndromes of infancy appear to have a good prognosis, respond to medical intervention and have had their genetic defect localized to a specific gene. Current advances promise reliable bedside techniques to measure central nervous system function, cerebral blood flow, endocrine hormones and receptors as well as glucose transporters and specific genetic defects. These data, when correlated with plasma glucose concentrations and central nervous system function and development, should provide a better understanding of the impact of prolonged and profound hypoglycemia on long-term outcome.