Periventricular-intraventricular hemorrhage (PV-IVH) remains the major cause of injury to the developing brain. Predisposing factors include a germinal matrix with an immature vasculature, a pressure passive cerebral circulation, and hemodynamic perturbations in sick premature infants. Intact cerebral autoregulation has been documented in stable premature infants; however, it functions within a limited blood pressure range and is likely to be absent in the sick hypotensive infant, which increases the risk for PV-IVH with perturbations in blood pressure. The risk for PV-IVH is markedly increased in the absence of antenatal glucocorticoid exposure in the intubated low birthweight infant <1000 g with respiratory distress syndrome; +/- other complications. Although surfactant administration reduces the severity of respiratory distress syndrome, it has not led to a reduction in PV-IVH. Early postnatal administration of indomethacin has been associated with a reduction in PV-IVH, although this has not translated into long-term neurocognitive benefits.