In prokaryotic and eukaryotic organisms, biochemical and physiological processes are sensitive to changes in H(+) activity. For these processes to function optimally, a variety of proteins have evolved that transport H(+)/base equivalents across cell and organelle membranes, thereby maintaining the pH of various intracellular and extracellular compartments within specific limits. The SLC4 family of base (HCO(3)(-), CO(3)(2(-))) transport proteins plays an essential role in mediating Na(+)- and/or Cl(-)-dependent base transport in various tissues and cell types in mammals. In addition to pH regulation, specific members of this family also contribute to vectorial transepithelial base transport in several organ systems including the kidney, pancreas, and eye. The importance of these transporters in mammalian cell biology is highlighted by the phenotypic abnormalities resulting from spontaneous SLC4 mutations in humans and targeted deletions in murine knockout models. This review focuses on recent advances in our understanding of the molecular organization and functional properties of SLC4 transporters and their role in disease.