The importance of intracellular and extracellular pH to physiological function is unquestioned. There are few scenarios in which pathological processes do not include aberrant pH. For example, cystic fibrosis, a genetic disease that adversely affects airways and other epithelia throughout the body, is associated with secretions that have abnormally low pH. Although the contributions of CO2 and HCO3− to acid–base balance have been known for well over a century and carbonic anhydrase was described first in The Journal of Physiology (Meldrum & Roughton 2012) some 80 years ago, much remains to be learned regarding the molecular and biophysical mechanisms that account for HCO3− transport and the resulting buffering capacity and pH regulation in most body compartments.