Bicarbonate, along with CO2, is the major pH buffer of biological fluids. A great majority of HCO3- reabsorption occurs via trans-cellular coupling of the luminal Na-H+-exchanger 3 and Na+-H+-ATPase with the basolateral Na+-HCO3- cotransporters (NBC). Several related proteins constitute the emerging NBC family (NBC1-3) of membrane cotransporters that are found in a variety of epithelial and non-epithelial tissues, and may be tissue specific. Physiologically, NBC is electrogenic, Na+ and HCO3- dependent, Cl- independent, and inhibited by stilbenes (DIDS and SITS). The NBC family of proteins are 30-35% related to anion exchangers (AE2 and AE3; SLC4A1-SLC4A3) and display the same protein topology: (a) At least 10 TM domains with both the N and C-termini predicted to be intracellular, (b) presence of a large, glycosylated, extracellular loop between TM5 and TM6; and (c) the lysine residues are conserved at predicted DIDS-reactive sites.