Periventricular leukomalacia in the premature infant is a lesion of cerebral white matter with its greatest period of risk when white matter is immature, that is, when oligodendrocyte precursors are proliferating and differentiating, and before myelin sheaths are actively synthesized. Although the pathogenesis of perinatal cerebral white matter damage involves multiple factors, the correlation of the timing of the lesion with dominance of oligodendrocyte precursors in cerebral white matter suggests that intrinsic factors related to oligodendrocyte precursors are critical. Ischemia and infection have both been implicated as causes of perinatal white matter damage. Major mechanisms underlying oligodendrocyte injury in ischemia include glutamate toxicity, free-radical injury, and cytokine damage mediated by macrophages accompanying ischemia-induced inflammation. Factors related to a vulnerability of immature oligodendrocytes to ischemia potentially include a developmental lack of antioxidant enzymes to mediate oxidative stress. Cytokine-mediated injury to oligodendrocytes is also potentially important. A complete understanding of the role of immature white matter in the pathogenesis of periventricular leukomalacia is essential for developing strategies to prevent it.