Therapeutic hypothermia (whole body or selective head cooling) is recognized as standard of care for brain injury control in term infants with perinatal hypoxic ischemic encephalopathy (HIE). Recent metanalyses and systematic reviews in human newborns have shown a reduction in mortality and long-term neurodevelopmental disability at 12-24 months of age, with more favourable effects in the less severe forms of HIE. HIE is most often noted in term newborns. Preterm infants can also suffer from HIE, but the clinical manifestations and pathology are different, involving subcortical gray matter injury in association with white matter damage. Several term and preterm animal experimental models showed that a reduction in brain temperature following a hypoxic-ischemic insult reduces energy expenditure and may reduce histological neuronal loss, but little is known on the safety of therapeutic hypothermia in preterm or very low birth weight (VLBW) infants. Hypothermia is one of the most promising future interventions for the treatment of acute ischemic stroke, and seems to improve survival and neurologic outcome after cardiac arrest in adults. Similarly, recent reviews have emphasized the possible role of therapeutic hypothermia after pediatric cardiac arrest, and a trial is ongoing to assess the benefits of induced hypothermia in pediatric traumatic brain injury. So far, there is a lack of data on other possible indications, i.e., neonates with stroke or after cardio-pulmonary resuscitation, and necrotizing enterocolitis. Carefully designed safety studies and large randomized trials for all the above conditions and especially for preterm infants should be planned.