This review emphasizes the importance of three endothelial-derived products in regulating fetal and transitional pulmonary vascular tone. Although the pathophysiologic events that culminate in PPHN are poorly understood, it is likely that endothelial cell dysfunction, with an alteration in the normal "balance" of endothelial-derived mediators, is a contributing factor. In addition to the three vasoactive mediators described herein, several other neurohumoral agents influence fetal and transitional pulmonary vascular tone. In addition, structural changes in the pulmonary circulation, with abnormal proliferation of smooth muscle and extracellular matrix components, also contribute to failure of normal postnatal adaptation. Continued research is necessary to better define the complex interactions that result in the normal transition from the fetal to the postnatal state. Continued advances in the understanding of the normal transition will allow a more rational approach to management of the failed transition reflected in the disease state, PPHN.