Thanks to recent progress in availability of molecular and functional techniques it became possible to search for the basic molecular and cellular processes that mediate and control HCO3- and fluid secretion by the pancreatic duct. The coordinated action of various transporters on the luminal and basolateral membranes of polarized epithelial cells mediates the transepithelial HCO3- transport, which involves HCO3- absorption in the resting state and HCO3- secretion in the stimulated state. The overall process of HCO3- secretion can be divided into two steps. First, HCO3- in the blood enters the ductal epithelial cells across the basolateral membrane either by simple diffusion in the forms of CO2 and H2O or by the action of an Na+-coupled transporter, a Na+-HCO3- cotranporter (NBC) identified as pNBC1. Subsequently, the cells secrete HCO3- to the luminal space using at least two HCO3- exit mechanisms at the luminal membrane. One of the critical transporters needed for all forms of HCO3- secretion across the luminal membrane is the cystic fibrosis transmembrane conductance regulator (CFTR). In the resting state the pancreatic duct, and probably other HCO3- secretory epithelia, absorb HCO3-. Interestingly, CFTR also control this mechanism. In this review, we discuss recent progress in understanding epithelial HCO3- transport, in particular the nature of the luminal transporters and their regulation by CFTR.