Although hypoxic-ischemic encephalopathy (HIE) is relatively rare, it commonly results in devastating long-term mortality and death. Intervention against this condition has been limited and frustrating. As research in this area progresses, a tremendous growth of knowledge about mechanisms involved with HIE is now contributing to the development of neuroprotective strategies. Hypothermia as a therapeutic intervention for HIE appears to be promising, as evident from recent human trials that suggest selective head cooling or total body cooling decreases the incidence of disability and death. Many questions, however, still remain unanswered about the use of hypothermia. Long-term efficacy and safety of hypothermia needs to be established before it can be recommended "as standard of care" for the treatment of neonatal HIE.