Persistent pulmonary hypertension of the newborn (PPHN) is a potentially life-threatening condition that is characterized by supra-systemic pulmonary vascular resistance causing right-to-left shunting through the ductus arteriosus and/or foramen ovale, leading to a vicious cycle of hypoxemia, acidosis and further pulmonary vasoconstriction. Advances in neonatology including surfactant instillation, high-frequency ventilation, extracorporeal membrane oxygenation and, most importantly, inhaled nitric oxide (INO), have revolutionized the management of PPHN. However, given that INO does not improve oxygenation in a significant proportion (30-40%) of cases, there is an urgent need to consider other therapeutic options for PPHN. The issue is more important for developing nations with a higher PPHN-related health burden and limited resources. This article discusses the evidence about INO in term and preterm neonates in brief, and focuses mainly on the potential alternative drugs in the management of PPHN.