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. Each body compartment is unique in its requirements for pH and buffering capacity. Thus, one of the great challenges for physiologists is to determine the components and regulatory cascades that can be incorporated into hypothetical models that account for each physiological setting. In this regard, recent work in The Journal of Physiology by Shan et al.(2012) assembles a tremendous amount of information and builds a solid foundation from which studies can be launched to understand further the regulation of airway surface volume, ionic composition and pH; the conclusions are likely to have applications for other cell and tissue systems. The authors used Calu-3 cells as an experimental model of the airway and employed a variety of robust assay systems to create a novel cellular model that is proposed to account for electrolyte and fluid secretion.