Although no specific pharmacologic therapy for clinical application to cerebral resuscitation after ischemia exists, biochemically guided mechanistic studies are under way to unravel what appears to be an extremely complex process. The evolution of the primary parenchymal insult after ischemia in the brain appears to be coupled to a multifactorial interaction between blood and damaged brain tissue that is initiated very rapidly during reperfusion and leads to further tissue injury (Fig. 8). Current studies implicate calcium, oxyradicals, phospholipid-derived metabolites, and blood elements as possible mediators of tissue injury during reperfusion. However, the optimal conditions for repair and ongoing metabolism after ischemia remain to be defined. In this regard, studies to investigate postischemic communication failure, optimal active and basal metabolic rate in the postischemic brain, and optimal pressure and flow patterns during reperfusion are needed to guide future therapies. Future therapies based on these alternative approaches could supplement refined versions of the regimens presented in this article--those that attempt to minimize reperfusion injury. Meaningful progress in the mitigation of postischemic encephalopathy is almost certain to require novel, specific therapies used in multimodal regimens with a significant fraction of the agents administered as near as possible to the onset of reperfusion. To develop these regimens to treat the pediatric arrest, studies in pediatric models or at least models of asphyxial arrest are essential.