An increase in cytosolic free Ca2+ concentration ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMCs) triggers pulmonary vasoconstriction and stimulates PASMC proliferation and migration leading to pulmonary artery wall thickening. In this study, we report that STIM2, a Ca2+ sensor in the sarcoplasmic reticulum (SR) membrane, is required for raising the resting [Ca2+]cyt in PASMCs from patients with pulmonary arterial hypertension (PAH) and activating downstream signaling cascades that stimulate PASMC proliferation and inhibit PASMC apoptosis. Downregulation of STIM2 in PAH-PASMCs by CRISPR/Cas9 reduces the resting [Ca2+]cyt, while overexpression of STIM2 in normal PASMCs increases the resting [Ca2+]cyt. The increased resting [Ca2+]cyt in PAH-PASMCs is associated with enhanced phosphorylation (p) of CREB, STAT3 and AKT, increased NFAT nuclear translocation, and elevated level of Ki67 (a marker of cell proliferation). Furthermore, the STIM2-associated increase in the resting [Ca2+]cyt also upregulates the anti-apoptotic protein Bcl-2 in PAH-PASMCs. Downregulation of STIM2 in PAH-PASMCs with siRNA a) decreases the level of pCREB, pSTAT3 and pAKT and inhibits NFAT nuclear translocation, thereby attenuating proliferation in PAH-PASMC, and b) decreases Bcl-2, which leads to an increase of apoptosis. In summary, these data indicate that upregulated STIM2 in PAH-PASMCs, by raising the resting [Ca2+]cyt, contributes to enhancing PASMC proliferation by activating the CREB, STAT3, AKT and NFAT signaling pathways and promoting quiescent PASMCs to enter the cell cycle and go through the mitosis. The STIM2-associated increase in the resting [Ca2+]cyt is also involved in upregulating Bcl-2 that makes PAH-PASMCs resistant to apoptosis, and thus plays an important role in sustained pulmonary vasoconstriction and excessive pulmonary vascular remodeling in patients with PAH.