Work in this and other laboratories over the last ten years has led to a better understanding of the mechanism of HCO3- secretion in the pancreatic duct, and particularly the role of CFTR in this process (Steward et al. 2005). It has also become clear that it is the loss of HCO3-, rather than Cl-, secretion that underlies much of the pathology of cystic fibrosis in the pancreas and in other affected tissues. Despite recent progress, a fundamental question remains unanswered: how is HCO3- secreted across the apical membrane at maximal rates when the luminal (secreted) concentration may exceed 140 mM? More specifically, does the CFTR channel itself provide the main route for HCO3- secretion across the apical membrane (Shcheynikov et al. 2004)? Or is the role of CFTR to promote the activity of a physically linked Cl–HCO3- exchanger (Ko et al. 2004)? In the pancreatic duct the apical anion exchanger is probably a member of the recently discovered SLC26 family (Mount & Romero, 2004). This is certainly involved in the initial stages of the secretory process when there is still a significant amount of Cl- present in the lumen. However, even allowing for the possibility that it might be electrogenic, it is difficult to see how such an exchanger could operate maximally when the luminal HCO3- concentration is as high as 140 mM. On the contrary, recent work on the pancreatic duct suggests that HCO3- is more likely to be secreted via an apical anion conductance under these conditions, most probably CFTR (see Ishiguro et al., this symposium). Previous work with the Calu-3 cell line, which is a good model for the serous cells of human airway submucosal glands, has also suggested that CFTR may act as a HCO3- channel and that this may be the main pathway for HCO3-, as well as Cl-, secretion in these cells (Hug et al. 2003). Nonetheless, our recent work suggests that an anion exchanger is also present in the apical membrane (Moore et al. 2005), that it is activated by CFTR, and that it shows many of the features of the SLC26 family. If so, this cell line may prove to be a useful experimental model for investigating the interactions between CFTR and the SLC26 exchangers during HCO3- secretion.