Persistent pulmonary hypertension of the newborn (PPHN) represents a challenging condition associated with significant morbidity. A successful transition from intrauterine to extrauterine life is contingent on adequate pulmonary vasodilation. Several pathophysiologies contribute to the failure of this cascade and may result in life-threatening hypoxia and acidosis in the newborn. Management includes optimal respiratory support, adequate sedation and analgesia, and support of vascular tone and cardiac function. Pulmonary vasodilation has the potential to overcome the cycle of hypoxia and acidosis, improving outcome in these infants. Oxygen and inhaled nitric oxide represent the foundation of therapy. Tertiary pulmonary vasodilators represent a greater challenge, selecting between therapies that include prostanoids, sildenafil, and milrinone. Variable levels of evidence exist for each agent. Thorough review of available data informing efficacy and adverse effects contributes to the development of an informed approach to neonates with refractory PPHN.