Recent developments in basic vascular biology have provided new insights into mechanisms contributing to pulmonary hypertension and novel approaches to its treatment. Although it has long been recognized that normal vascular endothelium produces endogenous vasodilators, identification of the so-called endothelium-derived relaxing factor as a gas, nitric oxide, led to extensive studies in several experimental models of pulmonary hypertension and in various clinical settings. Endogenous nitric oxide production modulates vascular tone in the fetal and postnatal lung, and contributes to the normal decline in pulmonary vascular resistance at birth. Exogenous (inhaled) nitric oxide therapy causes potent and selective pulmonary vasodilation in neonates with severe pulmonary hypertension (ie, persistent pulmonary hypertension of the newborn), as well as in patients with pulmonary hypertension due to congenital heart disease, acute hypoxemic respiratory failure, primary or unexplained pulmonary hypertension, and other diseases. The safety and efficacy of inhaled nitric oxide therapy is currently being examined in multicenter trials. Other endothelium-derived products, such as the potent vasoconstrictor peptide endothelin, may contribute to abnormal vascular tone, reactivity, and structure in the pulmonary circulation. Basic studies of mechanisms to altered vessel growth and remodeling may lead to further therapeutic strategies for chronic pulmonary hypertension.