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Hypoxic-ischemic brain injury occurs frequently in infancy and childhood. Events such as perinatal asphyxia, near drowning, respiratory arrest, and near sudden infant death syndrome Cause significant mortality and morbidity. Despite current critical care practices, the outcomes from such injuries may be life-long neurologic deficits. This review discusses findings from laboratory investigations into such injuries-in particular the roles of excitotoxic amino acids, proteolytic enzymes, free radicals, nitric oxide, and leukocytes. Understanding of the two distinct forms of neuronal death, necrosis and apoptosis, provides additional insights into mechanisms of injury. The development of new therapies for hypoxic-ischemic brain injury depends on such understanding. To date, the results of preclinical therapeutic trials have not demonstrated a “magic bullet‘ Nevertheless, the understanding of injury mechanisms has uncovered potential avenues for new therapies, particularly combination therapies or single interventions that have multiple effects. Clinical trials, using these strategies, are planned or have been recently begun and offer hope for advancements in treatment. Curr Opin Pediatr 1999, 11223–228 © 1999 Lippincott Williams & Wilkins. Inc.