There are several pulmonary hypertensive diseases that affect the neonatal population, including persistent pulmonary hypertension of the newborn (PPHN) and bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH). While the indication for inhaled nitric oxide (iNO) use is for late-preterm and term neonates with PPHN, there is a suboptimal response to this pulmonary vasodilator in ~40% of patients. Additionally, there are no FDA-approved treatments for BPD-associated PH or for preterm infants with PH. Therefore, investigating mechanisms that alter the nitric oxide-signaling pathway has been at the forefront of pulmonary vascular biology research. In this review, we will discuss the various mechanistic pathways that have been targets in neonatal PH, including NO precursors, soluble guanylate cyclase modulators, phosphodiesterase inhibitors and antioxidants. We will review their role in enhancing NO-signaling at the bench, in animal models, as well as highlight their role in the treatment of neonates with PH.