Bicarbonate and CO2 comprise the major pH buffer of biological fluids. In the renal proximal tubule most of the filtered HCO3- is reabsorbed by an electrogenic Na/HCO3 cotransporter located at the basolateral membrane. This Na+ bicarbonate cotransporter (NBC) was recently cloned. This review highlights the recent developments leading to and since the cloning of NBC: NBC expression cloning, protein features, clone physiology, isoforms and genes, mRNA distribution, and protein distribution. With the NBC amino acid sequence 30-35% identical to the anion exchangers (AE1-3), a superfamily of HCO3- transporters is emerging. Physiologically, NBC is electrogenic, Na+ dependent, HCO3- dependent, Cl- independent, and inhibited by stilbenes (DIDS and SITS). NBC clones and proteins have been isolated from several tissues (other than kidney) thought to have physiologically distinct HCO3- transporters. For example, NBC occurs in pancreas, prostate, brain, heart, small and large intestine, stomach, and epididymis. Finally, there are at least two genes that encode NBC proteins. Possible future directions of research are discussed.