The family of a-carbonic anhydrase (CA) enzymes is widely expressed in animal cells. Most members catalyse, in effect, the reversible hydration of CO2 to H+ and HCO3- anions, and in doing so influence ambient pH. Depending on its localisation and activity in a multicellular structure, a CA molecule can fulfil numerous roles in the spatial control of intracellular and local extracellular pH (pHi and pHe respectively). (i) In cardiac myocytes, epithelial enterocytes, and neurones, intracellular CA (eg. soluble cytoplasmic CA2 or certain other isoforms that are membrane- anchored) facilitates the spatial diffusion of cytoplasmic H+ ions, thereby regulating the uniformity of pHi, which assists in the spatial co-ordination of cell function. (ii) In non- vascularised or poorly perfused mulitcellular structures, such as experimentally seeded 3-D growths of tumour cells (25-50,000 cells), extracellular-oriented CA isoforms like CA9 can coordinate the spatial venting of metabolic CO2. This results in a relatively uniform and more alkaline intracellular pH within the growth, which may be selective for its survival. A comparable venting mechanism may plausibly assist the hibernation and survival of ischaemic myocardial tissue. By catalysing hydration of emergent CO2, exofacial CAs also tend to reduce pHe, which may enhance the invasiveness of a developing tumour. (iii) In isolated mammalian ventricular myocytes, intracellular but not extracellular CA activity facilitates the activity of generic sarcolemmal Na-HCO3 co- transport (NBC). This optimises the extrusion of cellular acid, and thus the regulation of cardiac pHi. Diffusion-reaction modelling suggests that CAi may achieve this by facilitating the spatial tunnelling of cytoplasmic H+ ions into the transport protein where they protonate imported HCO3- anions, thus promoting the alkalinisation of pHi. Interestingly, a similar facilitation of sarcolemmal Na-H exchange (NHE) by CAi cannot be observed in cardiac myocytes, suggesting that the CA-NBC transport metabolon is not supported by a comparable CA-NHE metabolon