Hypoxic-ischemic encephalopathy (HIE) due to neonatal asphyxia is an important cause of irreversible bad neurodevelopmental outcomes in children. Understanding the mechanisms causing the central nervous system cell death enabled the development of new treatment strategies that may decrease the severity of neurological damage. This survey includes data on epidemiology, pathogenesis, clinical features and diagnostic criteria of HIE. We discuss the neuro-protective mechanisms of therapeutic hypothermia and provide data on clinical studies conducted to investigate the impact and safety of this treatment in newborn infants affected by HIE. In addition, other therapeutic options of neuro-protective agents are mentioned.