Adenosine triphosphate (ATP) is a ubiquitous extracellular messenger elevated in the tumor microenvi- ronment. ATP regulates cell functions by acting on purinergic recep- tors (P2X and P2Y) and activating a series of intracellular signaling pathways. We examined ATP-induced Ca2 signaling and its effects on antiapoptotic (Bcl-2) and proapoptotic (Bax) proteins in normal human airway epithelial cells and lung cancer cells. Lung cancer cells exhibited two phases (transient and plateau phases) of increase in cytosolic [Ca2] ([Ca2]cyt) caused by ATP, while only the transient phase was observed in normal cells. Removal of extracellular Ca2 eliminated the plateau phase increase of [Ca2]cyt in lung cancer cells, indicating that the plateau phase of [Ca2]cyt increase is due to Ca2 influx. The distribution of P2X (P2X1-7) and P2Y (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11) receptors was different between lung cancer cells and normal cells. Proapoptotic P2X7 was nearly undetectable in lung cancer cells, which may explain why lung cancer cells showed decreased cytotoxicity when treated with high concentration of ATP. The Bcl-2/Bax ratio was increased in lung cancer cells following treatment with ATP; however, the antiapoptotic protein Bcl-2 dem- onstrated more sensitivity to ATP than proapoptotic protein Bax. Decreasing extracellular Ca2 or chelating intracellular Ca2 with BAPTA-AM significantly inhibited ATP-induced increase in Bcl-2/ Bax ratio, indicating that a rise in [Ca2]cyt through Ca2 influx is the critical mediator for ATP-mediated increase in Bcl-2/Bax ratio. Therefore, despite high ATP levels in the tumor microenvironment, which would induce cell apoptosis in normal cells, the decreased P2X7 and elevated Bcl-2/Bax ratio in lung cancer cells may enable tumor cells to survive. Increasing the Bcl-2/Bax ratio by exposure to high extracellular ATP may, therefore, be an important selective pressure promoting transformation and cancer progression.