Chronic nonneoplastic lung diseases that impair pulmonary oxygenation while increasing the levels of intrapulmonary carbon dioxide (CO2) are a documented risk factor for the development of lung cancer in smokers and nonsmokers. Using established cell lines derived from human small cell lung cancer (SCLC) and non-small cell lung carcinoma, our experiments demonstrated that elevated CO2 concentrations in the range of those found in the diseased lung selectively stimulated the proliferation of SCLC but not adenocarcinoma or squamous cell carcinoma. The proliferative response of SCLC cells involved activation of the mitogen-activated protein kinases ERK-1 and ERK-2, as well as the p70 ribosomal S6 kinase and the stimulation of an autocrine serotonergic loop. Kinase activation was unrelated to changes in intracellular pH. We concluded that CO2 is an important messenger molecule for SCLC which may contribute significantly to the high lung cancer burden observed in individuals with chronic lung disease, by the activation of kinases which play a central role as downstream effectors of many growth factor-stimulated mitogenic pathways.