Although neonatal brain injury occurs most frequently after a perinatal hypoxic-ischemic insult, recently studies have noted that variable causes such as metabolic and reperfusion events can result in, or aggravate, a brain insult. Current data suggest that about 2 to 5 of 1000 live births in the United States and more so in developing countries experience a brain injury Approximately 20% to 40% of infants who survive the brain injury develop significant neurological and developmental impairments. The resulting impact on the child, family, and society presents a formidable challenge to healthcare professionals. Although several important insights have been gained in the last several years about the epidemiology, diagnosis, and mechanism of brain injury, management remains mostly a cocktail of controversial trials. This article provides a comprehensive review of the pathology, clinical manifestations, and timely management of infants with brain injury.