Periventricular white matter injury, specifically cystic periventricular leukomalacia (PVL) and ipsilateral hemorrhage into white matter associated with periventricular-intraventricular hemorrhage (PV-IVH), contribute significantly to neonatal mortality and long-term neurodevelopmental deficits in the premature infant. The first lesion PVL occurs in approximately 3-4% of infants of birth weight (BW) < 1500 grams. It manifests either as a focal or diffuse lesion within white matter. Although the pathogenesis of PVL is complex and likely multifactorial, principle contributors include vascular factors which markedly increase the risk for ischemia during periods of systemic hypotension and the intrinsic vulnerability of the oligodendrocyte to neurotoxic factors such as free radicals or cytokines. Clinical associations with PVL include a history of chorioamnionitis, prolonged rupture of membranes, asphyxia, sepsis, hypocarbia, etc. The vast majority of infants exhibit long-term neurodevelopmental deficits that affect motor, cognitive and visual function. The second lesion, the ipsilateral hemorrhage into white matter lesion associated with PV-IVH, occurs in approximately 10-15% of infants of BW < 1000 grams. The white matter injury appears to be a venous infarction with hemorrhage occurring as a secondary phenomenon. Prevention of this lesion has to include prevention of the associated PV-IVH. In this regard, the antenatal administration of glucocorticoids has been associated with a significant reduction in the sonographic incidence of severe IVH and the associated white matter involvement. The postnatal administration of indomethacin to high risk infants appears to hold the most promise at the current time in preventing this lesion. The neurodevelopmental outcome with extensive white matter injury is universally poor, affecting long-term motor and cognitive deficits; the long-term outcome is more favorable with lesser involvement. A clearer understanding of pathogenesis of both conditions is essential so as to provide targeted preventative strategies.