Soluble adenylyl cyclase (sAC; ADCY10) is a bicarbonate (HCO3 -)-regulated enzyme responsible for the generation of cyclic adenosine monophosphate (cAMP). sAC is distributed throughout the cell and within organelles and, as such, plays a role in numerous cellular signalling pathways. Carbonic anhydrases (CAs) nearly instantaneously equilibrate HCO3 -, protons and carbon dioxide (CO2); because of the ubiquitous presence of CAs within cells, HCO3 --regulated sAC can respond to changes in any of these factors. Thus, sAC can function as a physiological HCO3 -/CO2/pH sensor. Here, we outline examples where we have shown that sAC responds to changes in HCO3 -, CO2 or pH to regulate diverse physiological functions.