Pulmonary arterial hypertension (PAH) is a severe and progressive disease that causes right heart failure. Recent studies suggested that the hypercontraction and excessive proliferation of the pulmonary artery induced by Ca²⁺ signaling abnormality may be involved in the pathogenesis of PAH, though their molecular mechanisms remain unclear. The Na⁺/Ca²⁺ exchanger (NCX) is a bidirectional transporter that is controlled by membrane potential and transmembrane gradients of Na⁺ and Ca²⁺. Vascular smooth muscle (VSM) NCX plays an important role in intracellular Ca²⁺ homeostasis and Ca²⁺ signaling. In this study, we investigated the pathophysiological roles of NCX1/2 in hypoxia-induced PAH, using VSM-specific NCX1/2 knockout mice and NCX1/2 inhibitors. VSM-specific NCX1-knockout mice exhibited attenuation of hypoxia-induced PAH and right ventricular hypertrophy compared with wild-type mice. In addition, administration of NCX1 inhibitors suppressed hypoxia-induced PAH and pulmonary vessel muscularization. These findings indicate that genetic knockout and pharmacologic inhibition of NCX1 attenuate the development of hypoxia-induced PAH. Furthermore, our next studies with VSM-specific NCX2-knockout mice will provide new evidence that NCX2 differentially contributes to the development of hypoxia-induced PAH.