Increasing evidence suggests that the pulmonary vascular endothelium is an important mediator of resting pulmonary vascular tone through the synthesis and release of a variety of vasoactive substances including nitric oxide (NO). In addition, pulmonary endothelial dysfunction (such as impairment of NO synthesis) is present in lung injury and may contribute to the pathophysiology of pulmonary hypertensive disorders. Recently, exogenously administered NO gas has been utilized to treat infants with persistent pulmonary hypertension of the newborn (PPHN). These preliminary studies suggest that inhaled NO is a promising new therapy for the treatment of infants with PPHN. Controlled clinical trials must now be performed to determine if the use of inhaled NO improves the long-term outcome of patients with PPHN. Long-term exposure must be monitored closely for potential toxicity which includes methemoglobinemia and lung injury secondary to peroxynitrite and nitrogen dioxide production.