The expression and function of the Na+/Ca2+ exchanger (NCX) in the regulation of intracellular Ca2+ homeostasis have been well studied in cardiac, skeletal, and systemic vascular myocytes, but not in pulmonary artery smooth muscle cells (SMCs). We have recently demonstrated that the NCX current is present in freshly isolated pulmonary artery SMCs using the patch-clamp technique. The current has a mean amplitude of 13 pA under near physiological resting conditions. The NCX may function in the forward mode to make a significant contribution to the decay of intracellular Ca2+ following Ca2+ release and/or depolarization. Hypoxic stimulation inhibits the NCX current, reduces the removal of intracellular Ca2+, and enhances Ca2+ release from the sarcoplasmic reticulum. Using RT-PCR, subcloning and sequence analysis, we have shown that three NCX1 splice variants: NCX1.2 (containing exons B, C, and D), NCX1.3 (exons B and D), and NCX1.7 (exons B, D, and F) are expressed in pulmonary artery smooth muscle. Each of these splice variants expressed in HEK293 cells it likely to show a distinct activity in the removal of intracellular Ca2+. Taken together, we provide clear evidence that NCX1 is functionally and molecularly expressed and plays a physiological role in pulmonary artery SMCs.