The purpose of this chapter is to briefly review selected aspects of the experimental basis for nitric oxide (NO) therapy of pulmonary hypertension and respiratory failure in pulmonary hypertension of the newborn (PPHN) and its potential role in treating severe respiratory distress syndrome (RDS) associated with prematurity. The chapter further summarizes current clinical data regarding the efficacy and safety of this treatment in term and preterm human neonates. Inhaled NO therapy for the premature neonate has been suggested with severe RDS with marked hypoxemia that persists despite surfactant therapy. The predominant mechanism underlying respiratory failure in the premature newborn is surfactant deficiency or dysfunction because of interactive effects of lung immaturity, lung injury, and pulmonary edema, which cause decreased lung compliance, diffuse atelectasis, and abnormal gas exchange. Surfactant therapy with mechanical ventilation improves lung compliance and gas exchange in most cases of RDS, improving their clinical course and outcome. Despite the success of surfactant therapy, some premature neonates with severe RDS fail to have sustained clinical improvement after surfactant treatment. Persistent hypoxemia despite multiple doses of surfactant has been estimated at up to 50%, depending on the criteria.