Elevated carbon dioxide is generally detrimental to animal cells suggesting an interaction with core processes in cell biology. We demonstrate that elevated carbon dioxide blunts G-protein activated cAMP signalling. The effect of carbon dioxide is independent of changes in intracellular and extracellular pH, independent of the mechanism used to activate the cAMP signalling pathway, and is independent of cell context. A combination of pharmacological and genetic tools demonstrated that the effect of elevated carbon dioxide on cAMP levels required the activity of the inositol triphosphate receptor. Consistent with these findings, carbon dioxide caused an increase in steady state cytoplasmic calcium concentrations not observed in the absence of the inositol triphosphate receptor or under non-specific acidotic conditions. We examined the well-characterized cAMP dependent inhibition of the isoform 3 Na+/H+ antiporter (NHE3) in kidney epithelial cells to demonstrate a functional relevance for carbon dioxide mediated reductions in cellular cAMP. Consistent with the cellular biochemistry, elevated carbon dioxide abrogated the inhibitory effect of cAMP on NHE3 function via an inositol triphosphate receptor dependent mechanism. We further expand on these findings through a discussion of the influence of carbon dioxide on the physiology of airways cells.