This review article discusses the pathogenesis of periventricular leukomalacia (PVL), the most common form of brain injury in premature infants. PVL is caused by ischemic injury to the cerebral white matter, primarily due to an incomplete vascular supply and maturation-dependent vulnerability of oligodendroglial (OL) precursor cells. These cells are particularly susceptible to free radical damage, especially during ischemia-reperfusion, and their death leads to the diffuse injury characteristic of PVL. Factors contributing to PVL include intraventricular hemorrhage, maternal/fetal infection or inflammation, and cytokines, which can increase local iron levels and generate reactive oxygen species. The pathogenesis also involves the maturation-dependent vulnerability of OL precursors, which are exquisitely sensitive to free radicals and iron accumulation. Prevention strategies include avoiding cerebral ischemia, using free radical scavengers, and administering antagonists for glutamate receptors. Maternal antibiotics or anticytokine agents may also help prevent injury from maternal/fetal infection. The article highlights the importance of early detection of impaired cerebrovascular autoregulation using near-infrared spectroscopy and the potential for interventions such as magnesium sulfate and glucocorticoids to prevent PVL. Overall, understanding the neurobiology of PVL is crucial for developing effective preventive measures.This review article discusses the pathogenesis of periventricular leukomalacia (PVL), the most common form of brain injury in premature infants. PVL is caused by ischemic injury to the cerebral white matter, primarily due to an incomplete vascular supply and maturation-dependent vulnerability of oligodendroglial (OL) precursor cells. These cells are particularly susceptible to free radical damage, especially during ischemia-reperfusion, and their death leads to the diffuse injury characteristic of PVL. Factors contributing to PVL include intraventricular hemorrhage, maternal/fetal infection or inflammation, and cytokines, which can increase local iron levels and generate reactive oxygen species. The pathogenesis also involves the maturation-dependent vulnerability of OL precursors, which are exquisitely sensitive to free radicals and iron accumulation. Prevention strategies include avoiding cerebral ischemia, using free radical scavengers, and administering antagonists for glutamate receptors. Maternal antibiotics or anticytokine agents may also help prevent injury from maternal/fetal infection. The article highlights the importance of early detection of impaired cerebrovascular autoregulation using near-infrared spectroscopy and the potential for interventions such as magnesium sulfate and glucocorticoids to prevent PVL. Overall, understanding the neurobiology of PVL is crucial for developing effective preventive measures.