Periventricular-intraventricular hemorrhage is an important problem, resulting in significant mortality and morbidity. Attempts to reduce this complication require an understanding of its pathogenesis. In this chapter a model was proposed, consisting of a series of events resulting in rapid changes of cerebral blood flow and intracranial pressure and leading to rupture of the unique fragile vessels of the germinal matrix and intraventricular regions. Understanding the beneficial physiologic changes induced by such agents such as phenobarbital and vitamin K and that such pharmacologic therapy must be started during the antenatal period has resulted in significant reductions of severe grades of IVH. Further prospective studies are needed to confirm these results using these two drugs alone and in combination. Other potentially beneficial drugs such as indomethacin should be investigated. Although the benefits of such therapy may improve perinatal outcome, the emphasis in our discipline should be the continued attempt to prevent the delivery of these VLBW infants.