At birth, a marked decrease in pulmonary vascular resistance allows the lung to establish gas exchange. Persistent pulmonary hypertension of the newborn (PPHN) occurs when this normal adaptation of gas exchange does not occur. We review animal models used to study the pathogenesis and treatment of PPHN. Both acute models, such as acute hypoxia and infusion of vasoconstrictors, and chronic models of PPHN created both before and immediately after birth are described. Inhaled nitric oxide is an important emerging therapy for PPHN. We review nitric oxide receptor mechanisms, including soluble guanylate cyclase, which produces cGMP when stimulated by nitric oxide, and phosphodiesterases, which control the intensity and duration of cGMP signal transduction. A better understanding of these mechanisms of regulation of vascular tone may lead to safer use of nitric oxide and improved clinical outcomes.