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.