Idiopathic pulmonary arterial hypertension (IPAH) is a rare, progressive, and fatal disease that predominantly affects women. The pathogenic mechanisms involved in the pulmonary vascular abnormalities (eg, arterial remodeling and sustained vasoconstriction) in IPAH patients remain unclear. A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) in pulmonary arterial smooth muscle cells (PASMCs) is an important stimulus for pulmonary vasoconstriction and PASMC migration and proliferation (which subsequently cause pulmonary vascular wall thickening leading to the increase in pulmonary vascular resistance). Increased resting [Ca2+]cyt and enhanced Ca2+ influx have been implicated in PASMCs from patients with IPAH. We examined whether the extracellular Ca2+-sensing receptor (CaSR), a unique G protein-coupled receptor (GPCR), is involved in the enhanced Ca2+ influx and proliferation in IPAH-PASMCs and whether blockade of CaSR inhibits experimental pulmonary hypertension. Approval to use the human lung tissues and cells was granted by the Institutional Review Board of University of Illinois at Chicago and all experiments were approved by the Ethics/Animal Care Committee of University of Illinois at Chicago. In normal PASMCs superfused with Ca2+-free solution, addition of 2.2 mmol/L Ca2+ to the perfusate had little effect on [Ca2+]cyt. In IPAH-PASMCs, however, restoration of extracellular Ca2+ induced a significant increase in [Ca2+]cyt. Extracellular application of spermine also markedly raised [Ca2+]cyt in IPAH-PASMCs but not in normal PASMCs. The calcimimetic R568 enhanced, whereas the calcilytic NPS2143 attenuated, the extracellular Ca2+-induced [Ca2+]cyt rise in IPAH-PASMCs. Furthermore, the protein expression level of CaSR in IPAH-PASMCs was greater than in normal PASMCs; knockdown of CaSR in IPAH-PASMCs with siRNA attenuated the extracellular Ca2+-mediated [Ca2+]cyt increase and inhibited IPAH-PASMC proliferation. Using animal models of pulmonary hypertension, our data showed that CaSR expression and function were both enhanced in PASMCs, whereas intraperitoneal injection of the calcilytic NPS2143 prevented the development of pulmonary hypertension and right ventricular hypertrophy in rats injected with monocrotaline and mice exposed to hypoxia. In conclusion, the extracellular Ca2+-induced increase in [Ca2+]cyt due to upregulated CaSR is a novel pathogenic mechanism contributing to the augmented Ca2+ influx and excessive PASMC proliferation in patients and animals with pulmonary arterial hypertension. Targeting CaSR in PASMCs may help develop novel therapeutic approach for pulmonary hypertension.