Cyclic AMP (cAMP) is an evolutionarily conserved regulator of metabolism. Recently, we identified a novel mammalian source of cAMP - soluble adenylyl cyclase (sAC) - that is regulated directly by bicarbonate ions (HCO(3)(-)). As the concentration of HCO(3)(-) reflects cellular levels of carbon dioxide (CO(2)), energy-generating metabolic processes (which increase intracellular CO(2)) are poised to activate bicarbonate-responsive sAC. This direct link between metabolic activity, sAC and cAMP could represent an evolutionarily conserved mechanism of metabolic feedback regulation.