Injury to the perinatal brain is a leading cause of childhood mortality and lifelong disability. Cerebral palsy and cognitive impairment are usually related to periventricular white matter damage, which is seen chiefly in babies born before 32 wk gestational age, and to corticosubcortical lesions, which occur mainly in full-term infants. Despite recent improvements in neonatal care, no effective treatment for perinatal brain lesions is available. Several interventions, such as magnesium sulfate in preterm newborns and hypothermia in term newborns, are the focus of completed or continuing clinical trials. Improved understanding of the pathophysiological mechanisms involved in perinatal brain lesions helps to identify potential targets for neuroprotective interventions, as discussed in this review.