The intercalated cell is an epithelial cell of the renal collecting tubule that is specialized for H+ and HCO3- transport. These cells exist as two types, alpha and beta. The alpha-cell secretes H+ into the lumen by an apical H(+)-ATPase and a basolateral Cl-/HCO3- exchanger that is a form of band 3 protein (AE1). The beta-cell secretes HCO3- into the lumen by an apical Cl-/HCO3- exchanger and a basolateral H(+)-ATPase. In a previous study, it was suggested that a reversal in epithelial polarity of these cells occurs during the response of the kidney to an acid load (G.J. Schwartz, J. Barasch, and Q. Al-Awqati. Nature Lond. 318: 368-371, 1985). Recent studies, however have shown that there are many other subtypes where the distribution of these two proteins does not fit into this neat bipolar classification. This group of investigators recently generated an immortalized cell line of the beta-intercalated cell and found that the apical Cl-/HCO3- exchanger is also AE1. Furthermore, when these cells were seeded at high densities, the polarized targeting of the apical band 3 was reversed to the basolateral membrane. This was produced by the secretion of extracellular matrix protein that by themselves were capable of reversing the polarity of band 3 (J. S. van Adelsberg, J. C. Edwards, J. Takito, B. Kiss, and Q. Al-Awqati. Cell 76: 1053-1061, 1995). A large new extracellular matrix protein, hensin, was identified and found to be present exclusively in the collecting tubule. The extensive recent literature on the biology of alpha- and beta-intercalated cells is reviewed here and found to be compatible with the idea of the reversal of polarity as a mechanism for the regulation of H+ secretion by the tubule.