Injury to the premature brain is a major contributor to infant mortality and morbidity, often leading to mental retardation and sensory-motor impairment. The disease process is believed to be caused, sustained, and aggravated by multiple perinatal factors that team up in a multi-hit fashion. Clinical, epidemiological, and experimental studies have revealed that key factors such as inflammation, excitotoxicity, and oxidative stress contribute considerably to white- and gray-matter injury in premature infants, whose brains are particularly susceptible to damage. Depending on the timing, lesions of the immature brain may influence developmental events in their natural sequence and redirect subsequent development. We review current concepts on molecular mechanisms underlying injury to the premature brain.