There are two principal lesions that underlie brain injury and the neurologic manifestations in the premature infant: periventricular hemorrhagic infarction and periventricular leukomalacia. Both of these lesions may be potentially preventable: periventricular hemorrhagic infarction by preventing germinal matrix-IVH, and periventricular leukomalacia by detecting impaired cerebrovascular regulation with near-infrared spectroscopy, preventing the impaired cerebral blood flow and interrupting the cascade to oligodendroglial cell death, perhaps by such agents as free-radical scavengers. Prenatal magnesium sulfate also may be valuable. The greatest progress toward prevention has been made regarding periventricular hemorrhagic infarction, but the advent of new technologies, especially near-infrared spectroscopy, and of new insights into the cellular basis for oligodendroglial vulnerability provide hope for prevention of periventricular leukomalacia.