Most pancreatic secretory proteins are packaged within the trans-Golgi network into zymogen granules, which are secreted in a regulated manner by exocytosis. But others enter alternative, constitutive-like pathways directed towards both apical and basolateral membranes. Our in-vivo studies suggest that secretion via the latter type of pathway, which may be responsible for the appearance of pancreatic enzymes in the circulation, can be increased by stimulation, especially supramaximal stimulation. This may partly explain the increased concentration of pancreatic enzymes in the circulation in the early stages of pancreatitis. The mechanisms by which secretory proteins are sorted into zymogen granules remain vague. However, dissipation of the normally acidic gradient across the trans-Golgi network in vitro (e.g. with NH4Cl) inhibits the process by which newly synthesized proteins reach zymogen granules. However, secretion via the constitutive-like pathways is apparently not increased under these conditions. Thus, although the acidic milieu of the trans-Golgi network plays a role in pancreatic protein sorting, it may not be the mechanism by which constitutive-like secretion of pancreatic enzymes is increased.