Neonatal encephalopathy remains a significant cause of death and disability worldwide. Therapeutic
hypothermia has become a mainstay of therapy and has demonstrated the potential for neuroprotection and repair after
neonatal hypoxic-ischemic brain injury. However, it has become apparent from published trials that hypothermia alone
will not serve as complete protection nor benefit all neonates. The complicated cascade of events in a hypoxic-ischemic
insult lends itself to multiple types of therapy, making a multi-faceted approach to treatment attractive. This review
critically discusses the broad range of medical therapies currently being studied and summarizes the animal and human
studies that have been done to date. Therapies that may act synergistically with cooling therapy are also discussed.