Transepithelial Cl(-) and HCO(3)(-) transport is critically important for the function of all epithelia and, when altered or ablated, leads to a number of diseases, including cystic fibrosis, congenital chloride diarrhea, deafness, and hypotension (78, 111, 119, 126). HCO(3)(-) is the biological buffer that maintains acid-base balance, thereby preventing metabolic and respiratory acidosis (48). HCO(3)(-) also buffers the pH of the mucosal layers that line all epithelia, protecting them from injury (2). Being a chaotropic ion, HCO(3)(-) is essential for solubilization of ions and macromolecules such as mucins and digestive enzymes in secreted fluids. Most epithelia have a Cl(-)/HCO(3) exchange activity in the luminal membrane. The molecular nature of this activity remained a mystery for many years until the discovery of SLC26A3 and the realization that it is a member of a new family of Cl(-) and HCO(3)(-) transporters, the SLC26 family (73, 78). This review will highlight structural features, the functional diversity, and several regulatory aspects of the SLC26 transporters.