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Despite advancements in neonatal intensive care, the prognosis for infants with hypoxic-ischemic brain injury remains poor. Hypoxic-ischemic brain injury is a subset of neonatal encephalopathy that manifests following the disruption of cerebral blood flow and oxygen in the term or near-term infant. The degree of cerebral blood flow impairment caused by this insult dictates the timing and mode of cell death (necrosis or apoptosis) and the ensuing degree and type of brain injury. Modest systemic or selective hypothermia of the brain by as little as 2–4°C has been shown to reduce the extent of tissue injury in experimental as well as human studies after events such as stroke, trauma or cardiac arrest. Two large randomized clinical trials in neonates have recently been published. Both have demonstrated a reduction in the combined outcome of death or neurological disability. Other randomized clinical trials are in progress. Given the potential risks of cooling and rewarming, it is important for centers that wish to make it standard of care to have their physicians trained in the use of total body or selective head cooling. All cooled infants should be entered into a registry and it is the responsibility of each center to provide long-term follow-up.Journal of Perinatology (2007) 27, S47–S58. doi:10.1038/sj.jp.7211729 [ABSTRACT FROM AUTHOR]