The cerebral metabolic responses to perinatal hypoglycemia and anoxia were studied in newborn rats given regular insulin (30 units per kilogram of body weight). Animals were observed for up to 2 hours with no apparent ill effects in spite of blood glucose concentrations of 0.75 mmol per liter. When exposed to 100% nitrogen at 37°C, hypoglycemic animal survived only one-tenth as long as littermate controls with normal blood glucose levels (4.7 mmol/L). Pretreatment of hypoglycemic rats with glucose (10 mmol/kg) 10 and 30 minutes prior to nitrogen exposure nearly completely reversed the anoxic vulnerability. Hypoglycemia led to progressive reductions in crebral glycogen and glucose; however, only glucose reverted to normal levels 20 minutes after systemic glucose administration. The glycolytic intermediates glucose 6-phosphate and lactate were also lower during hypoglycemia. Brain glucose levels below 0.1 mmol per kilogram were associated with a disrupted cerebral energy state, reflected by declines in phosphocreatine (33%) and adenosine triphosphate (ATP) (10%). Cerebral energy utilization (metabolic rate) was minimally reduced (−7.2%) by hypoglycemia and returned to the control value (2.36 mmol ∼ P/kg/min) with glucose treatment. The cerebral energy reserves ATP, adenosine diphosphate, and phosphocreatine delined more rapidly and to a lower level in hypoglycemic rats subjected to 2 1/2 minutes of anoxia than in normoglycemic animals rendered similarly hypoxic. The findings suggest that decreased anoxic resistance of hypoglycemic newborn rats is not primarily a function of reduced brain glycogen or altered cerebral metabolic rate. The presence of endogenous cerebral glucose stores combined with continued circulating glucose (cerebrovascular perfusion) appear to be critical factors for maintaining perinatal hypoxic survival.