This article, part of a series on the developmental biology of the nervous system, focuses on periventricular leukomalacia (PVL), a major form of brain injury in premature infants. Dr. Joseph J. Volpe discusses the pathogenesis of PVL, highlighting factors that predispose infants to this disorder and potential methods of prevention. PVL is characterized by focal and diffuse injuries, with the focal component involving localized necrosis and the diffuse component affecting oligodendroglial (OL) precursor cells. The pathogenesis of PVL involves several interacting factors, including vascular anatomic and physiological factors, impaired cerebrovascular autoregulation, and the maturation-dependent vulnerability of OL precursors to ischemia and free radical attack. Recent studies suggest that intraventricular hemorrhage, maternal/fetal infection, inflammation, and cytokines may contribute to PVL by increasing iron concentrations and generating reactive oxygen species. The article also explores potential preventive interventions, such as avoiding cerebral ischemia through detection of infants with impaired cerebrovascular autoregulation, using free radical scavengers, and administering antagonists of glutamate receptors or neurotrophic factors. The combination of these interventions may prove most effective in preventing PVL.This article, part of a series on the developmental biology of the nervous system, focuses on periventricular leukomalacia (PVL), a major form of brain injury in premature infants. Dr. Joseph J. Volpe discusses the pathogenesis of PVL, highlighting factors that predispose infants to this disorder and potential methods of prevention. PVL is characterized by focal and diffuse injuries, with the focal component involving localized necrosis and the diffuse component affecting oligodendroglial (OL) precursor cells. The pathogenesis of PVL involves several interacting factors, including vascular anatomic and physiological factors, impaired cerebrovascular autoregulation, and the maturation-dependent vulnerability of OL precursors to ischemia and free radical attack. Recent studies suggest that intraventricular hemorrhage, maternal/fetal infection, inflammation, and cytokines may contribute to PVL by increasing iron concentrations and generating reactive oxygen species. The article also explores potential preventive interventions, such as avoiding cerebral ischemia through detection of infants with impaired cerebrovascular autoregulation, using free radical scavengers, and administering antagonists of glutamate receptors or neurotrophic factors. The combination of these interventions may prove most effective in preventing PVL.