Neonatal extracorporeal support is most often required for neonatal hypoxemic respiratory failure, usually accompanied by persistent pulmonary hypertension of the newborn (PPHN). PPHN is a clinical syndrome that results from the failure of pulmonary vascular transition to extrauterine life. Infants typically present shortly after birth with respiratory distress and cyanosis, but a structurally normal heart. The incidence of PPHN is estimated at 0.2% of live-born term infants. Respiratory failure and hypoxemia in the term newborn result from a heterogeneous group of disorders, and the therapeutic approach and response often depend on the underlying disease. PPHN can largely be thought of as one of three types: (1) the abnormally constricted pulmonary vasculature which is the most common type and includes diagnoses such as meconium aspiration syndrome, respiratory distress syndrome, and sepsis; (2) the structurally abnormal vasculature, which is often termed idiopathic PPHN; or (3) the hypoplastic vasculature such as is seen in congenital diaphragmatic hernia, or alveolar capillary dysplasia, a rare malformation of lung development. The pathophysiology of each type is dependent on the point in gestation when the normal transition to extrauterine life fails. This article will discuss the known pathophysiology in PPHN and new treatment modalities.