Hypoxic-ischemic encephalopathy is a subtype of neonatal encephalopathy and a major contributor to global neonatal morbidity and mortality. Despite advances in obstetric and neonatal care there are still challenges in accurate determination of etiology of neonatal encephalopathy. Thus, identification of intrapartum risk factors and comprehensive evaluation of the neonate is important to determine the etiology and severity of neonatal encephalopathy. In developed countries, therapeutic hypothermia as a standard of care therapy for neonates with hypoxic-ischemic encephalopathy has proven to decrease incidence of death and neurodevelopmental disabilities, including cerebral palsy in surviving children. Advances in neuroimaging, brain monitoring modalities, and biomarkers of brain injury have improved the ability to diagnose, monitor, and treat newborns with encephalopathy. However, challenges remain in early identification of neonates at risk for hypoxic-ischemic brain injury, and determination of the timing and extent of brain injury. Using imaging studies such as Neonatal MRI and MR spectroscopy have proven to be most useful in predicting outcomes in infants with encephalopathy within the first week of life, although comprehensive neurodevelopmental assessments still remains the gold standard for determining long term outcomes. Future studies are needed to identify other newborns with encephalopathy that might benefit from therapeutic hypothermia and to determine the efficacy of other adjunctive neuroprotective strategies. This review focuses on newer evidence and advances in diagnoses and management of infants with neonatal encephalopathy, including novel therapies, as well as prognostication of outcomes to childhood.