Phosphodiesterases (PDEs) are important components in cellular signaling in many vascular beds. Although the most recognized PDE inhibitor, sildenafil, a specific PDE5 inhibitor, is best known for its effect on the penile vascular bed resulting in erection, it also has therapeutic effects in other vascular beds, including the coronary and pulmonary vasculature. The first large, randomized, double-blind, placebo-controlled clinical trial using sildenafil in patients with pulmonary arterial hypertension was reported in 2005. As a result of this and other studies, sildenafil is now used to treat idiopathic pulmonary hypertension. Future studies are required to assess the potential use of other PDE5 antagonists and combination therapy on pulmonary hemodynamics, functional capacity, and long-term prognosis in the treatment of pulmonary arterial hypertension.