Neonatal hypoglycemia is of frequent occurrence in fasted newborn babies or animals but the origin of this hypoglycemia is not fully understood. Studies performed in newborn rats have shown that liver glycogenolysis and gluconeogenesis occur immediately after birth and that the increase in the activities of key regulatory enzymes (phosphorylase, glycogen synthetase and phosphoenolpyruvate carboxykinase) results probably from the rise of plasma glucagon and the fall of plasma insulin induced by the "stress" of birth. When the liver glycogen stores have been exhausted, i.e. between 6 and 16 hours after birth, a profound hypoglycemia develops in fasting newborn rats. The inability of hepatic gluconeogenesis to produce sufficient glucose to meet the energy requirement of the newborn tissues results from a lack of fat-derived (free fatty acids and ketone bodies) and gluconeogenic (lactate, amino acids) substrates. The stage of appearance and the mechanisms regulating gluconeogenesis in other species including human are discussed.