Neonatal brain injury remains a common cause of developmental disability, despite tremendously enhanced obstetrical and neonatal care. The timing of brain injury occurs throughout gestation, labor, and delivery, providing an evolving form of brain injury and a moving target for therapeutic intervention. Nonetheless, markedly improved methods are available to identify those infants injured at birth, via clinical presentation with neonatal encephalopathy and neuroimaging techniques. Postischemic hypothermia has been shown to be of tremendous clinical promise in several completed and ongoing trials. As part of this approach to the treatment of the newborn, other parameters of physiologic homeostasis can and should be attended to, with strong animal and clinical evidence that their correction will have dramatic influence on the outcome of the newborn infant. This review addresses aspects of newborn care to which we can direct our attention currently, and which should result in a safe and efficacious improvement in the prognosis of the newborn with neonatal encephalopathy.