Soluble adenylyl cyclase (sAC) is a source of the second messenger cyclic adenosine 3', 5' monophosphate (cAMP). sAC is directly regulated by bicarbonate (HCO(-) 3) ions. In living cells, HCO(-) 3 ions are in nearly instantaneous equilibrium with carbon dioxide (CO2) and pH due to the ubiquitous presence of carbonic anhydrases. Numerous biological processes are regulated by CO2, HCO(-) 3, and/or pH, and in a number of these, sAC has been shown to function as a physiological CO2/HCO3/pH sensor. In this review, we detail the known pH sensing functions of sAC, and we discuss two highly-studied, pH-dependent pathways in which sAC might play a role.