Alcohol induces Ca2+-dependent intracellular trypsinogen activation in the apical granular area via non-oxidative metabolites, such as fatty acid ethyl esters and fatty acids. Intracellular trypsinogen activation is a crucial initiating event in the development of acute pancreatitis, but the specific organelle in which this process takes place has been unknown. Recent data demonstrate that the Ca2+-dependent trypsinogen activation occurs in postexocytotic endocytic vacuoles. These vacuoles are acid due to a bafilomycin-sensitive vacuolar H+ ATPase and have a very Ca2+-permeable membrane. Acid endocytic structures, together with lysosomes, zymogen granules and elements of the endoplasmic reticulum, also play an important role in the physiological Ca2+ signal generation that normally regulates enzyme and fluid secretion from the exocrine pancreas.