Idiopathic pulmonary arterial hypertension (IPAH) remains a devastating and deadly disease with a poor long-term prognosis. The median survival for untreated patients is only 2.8 years, with pitiful three-year, five-year, and seven-year survival rates of 68%, 57%, and 49%, respectively.1The goal of a breakthrough discovery leading to a meaningfully life-extending treatment protocol has not yet been achieved, as the exact pathogenic mechanisms of pulmonary arterial hypertension (PAH) are too complex for current understanding. Research has, on the bright side, yielded a promising, increasingly detailed map of disease processes. Endothelium-derived nitric oxide (NO) is a major vasodilator, while its downstream effectors, cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG), have been demonstrated to cause vasodilative, anti-proliferative, anti-coagulant, and anti-inflammatory effects on pulmonary vasculature. Therefore, the L-arginine-NO-cGMP-PKG signaling cascade is an important pathway for developing therapies for PAH (Fig. 1).