The management of PPHN entered a new era with the development of inhaled NO therapy for the relief of pulmonary hypertension. The wider application of INO therapy and improved ventilation strategies led to a decrease in the need for invasive life-sustaining therapies such as ECMO. The remarkable advances in the understanding and treatment of PPHN were made possible by the extensive investigations in the laboratory using animal models. Further decreases in morbidity and mortality are possible with specific strategies targeted to correct the alterations in NO and prostacyclin biology and strategies to reduce lung injury. Further research is needed to understand the basis for the biologic susceptibility of some infants to environmental insults such as intra-uterine stressor exposure to NSAIDs in utero.