Persistent pulmonary hypertension of the newborn (PPHN) contributes significantly to the morbidity and mortality associated with meconium aspiration syndrome. This review article discusses new insights into the vascular abnormalities that are associated with PPHN, including the recent recognition of the importance of oxidant stress in its pathogenesis. Recent data are presented showing that treatment with high oxygen concentrations may increase production of oxygen free radicals. The rationale for the use of inhaled nitric oxide, and strategies for enhancing nitric oxide signaling are discussed. Finally, the rationale for new treatment approaches is reviewed, including inhibition of cyclic guanosine monophosphate-specific phosphodiesterases and scavengers of reactive oxygen species.