The most common form of brain injury in preterm infants is focal necrosis and gliosis of the periventricular white matter, generally referred to as periventricular leukomalacia (PVL). PVL is also the most common cause of cerebral palsy in preterm infants. Although the incidence of the most severe cystic form of PVL is decreasing, a more subtle diffuse form has emerged as the much more common lesion, possibly related to the increased survival of the smallest, most vulnerable infants. Experimental data suggest the central theme of pathogenesis is the effect of hypoxia, ischemia, and inflammation on the oligodendrocyte progenitor cell, the primary cellular target of PVL. Innovative experimental models and clinical trials using magnetic resonance imaging continue to shed light on the mechanisms of brain injury involved in PVL and provide the basis for future neuroprotective strategies. This review presents the neuropathology, pathogenesis, clinical presentation, diagnosis, and outcome of PVL.