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Persistent pulmonary hypertension of the neonate (PPHN) refractory to inhaled nitric oxide still represents a frequent clinical challenge with negative outcomes in neonatal critical care. Several pulmonary vasodilators have become available thanks to improved understanding of pulmonary hypertension pathobiology. These drugs are commonly used in adults and there are numerous case series and small studies describing their potential usefulness in neonates, as well. New vasodilators act on different pathways, some of them can have additive effects and all have different pharmacology features. This information has never been summarized so far and no comprehensive pathobiology-driven algorithm is available to guide the treatment of refractory PPHN. Conclusion : We offer a rational clinical algorithm to guide the treatment of refractory PPHN based on expert advice and the more recent pathobiology and pharmacology knowledge. What is Known: • Refractory PPHN occurs in 30–40% of iNO-treated neonates and represents a significant clinical problem. Several pulmonary vasodilators have become available thanks to a better understanding of pulmonary hypertension pathobiology. What is New: • Available vasodilators have different pharmacology, mechanisms of action and may provide additive effect. We provide a rational clinical algorithm to guide the treatment of refractory PPHN based on expert advice and the more recent pathobiology and pharmacology knowledge .