Very recent studies in adult gerbils and rats have shown that exposure to sublethal ischemia can confer neuroprotection from subsequent lethal ischemic episodes. To determine if a similar phenomenon can be elicited during the perinatal period, we have developed a preconditioning regimen that involves exposure to normothermic hypoxia (8% oxygen) 24 h prior to hypoxia-ischemia in the well-established post-natal-day 7 rat pup model [20]. Significant infarction, manifested as a 34 ± 4% reduction in cerebral hemispheric weight ipsilateral to the carotid ligation, was noted in control animals (n = 24) one week after hypoxia-ischemia, whereas littermates preconditioned with 3 h hypoxia (n = 29) showed no evidence of hemispheric necrosis. Lack of injury in the latter animals was confirmed at the cellular level by histopathologic analyses of Nissl-stained coronal sections. Thus, pre-exposure to hypoxia induces endogenous adaptive mechanisms that can protect the perinatal brain from hypoxic-ischemic injury.