Brain injury secondary to hypoxic-ischemic disease is the predominant form of all brain injury encountered in the perinatal period. The focus of this article is the most recent research developments in this field and especially those developments that should lead to the most profound effects on interventions in the first years of the new millennium. Neuronal injury is the predominant form of cellular injury in the term infant. The principal mechanisms leading to neuronal death after hypoxia-ischemia/reperfusion are initiated by energy depletion, accumulation of extracellular glutamate, and activation of glutamate receptors. The cascade of events that follows involves accumulation of cytosolic calcium and activation of a variety of calcium-mediated deleterious events. Notably this deleterious cascade, which evolves over many hours, may be interrupted even if interventions are instituted after termination of the insult, an important clinical point. Of the potential interventions, the leading candidates for application to the human infant in the relative short-term are mild hypothermia, inhibitors of free radical production, and free radical scavengers. Promising clinical data are available for the use of mild hypothermia.