Abstract： Pancreatic duct cells secrete HCO3- ions into a HCO3--rich luminal fluid (～140 mmol/L in human) against at least a 6-fold concentration gradient. Candidate mechanisms for HCO3- transport across the apical membrane include Cl--HCO3- exchange by an SLC26 anion transporter and diffusion via the HCO3- conductance of cystic fibrosis transmembrane conductance regulator (CFTR).Members of the SLC26 family are known to mediate Cl--HCO3- exchange across the apical membrane of other epithelia and both SLC26A6 and SLC26A3 have been detected in pancreatic ducts. Co-expression studies have also revealed that murine slc26a6 and slc26a3 physically interact with CFTR through the STAS domain of slc26 and the R domain of CFTR, resulting in mutually enhanced activity. Other studies have indicated that these exchangers are electrogenic: slc26a6 mediating 1Cl--2HCO3- exchange and slc26a3 mediating 2Cl--1HCO3- exchange. Recent experiments using isolated pancreatic ducts from slc26a6~- mice suggest that slc26a6 mediates most of the Cl--dependent secretion of HCO3- across the apical membrane in the mouse and the data are consistent with the reported electrogenicity of slc26a6. However, the role of SLC26A6 in human pancreatic HCO3- secretion is less clear because human ducts are capable of secreting much higher concentrations of HCO3-. The role of SLC26A6 must now be evaluated in a species such as the guinea pig which, like the human, is capable of secreting HCO3- at a concentration of ～140 mmol/L. From existing guinea pig data we calculate that a 1Cl--2HCO3- exchanger such as slc26a6 would be unable to secrete HCO3- against such a steep gradient. On the other hand, the HCO3- conductance of CFTR could theoretically support secretion of HCO3- to a much higher concentrations. CFTR may therefore play a more important role than SLC26A6 in HCO3- secretion by the guinea pig and human pancreas.