Clinical and experimental observations suggest that acidic environment in the pancreatic lumen may increase the risk of developing acute pancreatitis. The luminal pH is mainly regulated by both acinar and ductal cells. Acinar cells secrete digestive enzymes and protons which leads to acidification in the acinar lumen (Behrendorff et al., 2010). The high proton concentration inside the lumen can distrupt intercellular junctional links which may be involved in the initiation or development of acute pancreatitis. In contrast to acinar cells, ductal cells secrete a bicarbonate-rich alkaline solution (Argent, 2006) which neutralizes the stomach acidic chyme. It has been recently highlighted that this alkaline fluid is responsible for the neutralization of the extracellular pH in the acinar lumen as well (Freedman et al., 2001). The luminal proton, secreted by acinar cells may act as a paracrine messenger on the ductal cells and stimulate ductal bicarbonate secretion via acid-sensing ion channels (ASICs) (Holzer et al., 2007). The defect in ductal bicarbonate secretion, which occurs in certain pancreatic diseases (such as cystic fibrosis) can increase the risk to pancreatitis (Hegyi et al., 2011). Recent studies on ductal cells suggest that toxic factors, such as bile acids (Venglovecz et al., 2008) or ethanol (Yamamoto et al., 2003) also inhibit pancreatic ductal bicarbonate secretion which acidifies the lumen of the ducts and slows down the washout of the digestive enzymes. In summary, characterization of the ductal acid sensing mechanisms is essential to understand the acinar-ductal functional unit and may improve our knowledge in the pathomechanism of pancreatitis.