Pulmonary hypertension in the neonate is associated with multiple underlying problems such as respiratory distress syndrome, meconium aspiration syndrome, congenital diaphragmatic hernia, bronchopulmonary dysplasia, sepsis, or congenital heart disease. Because of the heterogeneous group of disorders, the therapeutic approach and response often depends on the underlying disease. In many of these conditions, there is evidence that cyclic nucleotide signaling and specifically phosphodiesterases (PDEs) are disrupted. PDE inhibitors represent an emerging class of pulmonary vasodilators in adults. Studies are now under way to evaluate the utility, efficacy, and safety of such therapies in infants with pulmonary hypertension.