Hypothermia therapy is the standard treatment for hypoxic ischemic encephalopathy (HIE). Mild hypothermia between 34-35°C is initiated within 6 hours and continued for at least 72 hours. This decreases cerebral metabolic rate, excitatory neurotransmitter release, apoptosis, and vascular permeability. Hypothermia reduces mortality and neurodevelopmental disability in HIE. Other promising therapies target oxidative stress, calcium channels, excitatory amino acids, nitric oxide, and apoptosis, but require further study. Stem cell transplantation may also have potential as a future regenerative therapy for HIE.