This chapter will report to the frequency of neonatal hypoxic-ischemic encephalopathy. The pathophysiology and the childhood outcome of encephalopathy due to hypoxia-ischemia will be examined. The limitations of current therapy for this condition and new therapies will be evaluated. Hypothermia seems to offer the most promise as a therapy for neuroprotection in hypoxic-ischemic encephalopathy. The evidence-based trials of hypothermia will be reviewed along with recommendations regarding clinical applications for this therapy and need for long-term follow-up of children receiving this therapy.