Neonatal encephalopathy due to perinatal hypoxia-ischemia (hypoxic-ischemic encephalopathy [HIE]) occurs at a rate of 1 to 3 per 1000 live births. Therapeutic hypothermia is the standard of care and the only currently available therapy to reduce the risk of death or disability in newborns with moderate to severe HIE. Hypothermia therapy needs to be initiated within 6 hours after birth in order to provide the best chance for neuroprotection. All pediatricians and delivery room attendants should be trained to recognize encephalopathy and understand the eligibility criteria for treatment. The modified Sarnat examination is the most frequently used tool to assess the degree of encephalopathy and has six categories, each of which can have mild, moderate, severe abnormalities. Apart from historical and biochemical criteria, a neonate must have 3 of 6 categories scored in the moderate or severe range in order to qualify for hypothermia as was done in the randomized trials. Whether an infant qualifies or there is concern that an infant might have HIE, transfer to a center that can perform treatment should be initiated immediately. Hypothermia significantly reduces the risk of death or moderate to severe impairments at 2 years and at school age. On average, only 7 neonates need to be treated for one neonate to benefit. Although easy in concept, implementation of hypothermia does require expertise and should be carried out under the guidance of a neonatologist. If infants are passively cooled prior to transport, core temperature needs to be closely monitored with a target of 33.5°C ± 0.5°C. Maintenance of homeostasis is important in order to prevent conditions that may result in additional brain injury. Seizures are common in neonates with HIE, but electrographic seizures are rare in the first few hours after birth if the insult occurred during labor and delivery. Prophylactic antiepileptic drugs should not be administered. Brain monitoring in the form of electroencephalogram (EEG) and or amplitude-integrated EEG should be implemented as soon as possible to help with prognosis and to accurately diagnose seizures.