In vitro and in vivo studies indicate that the secretory response to both caerulein and carbamylcholine stimulation is biphasic. Over the range of submaximal to maximal concentrations of secretagogues, discharge of exocrine proteins in vitro into the incubation medium and in vivo into the pancreatic duct increased and morphologic analysis indicated that exocytosis of zymogen granules occurred exclusively at the luminal membrane. Under in vivo conditions, supramaximal stimulation with caerulein or carbamylcholine resulted in a dosedependent decrease in amylase release into the pancreatic duct and increase in the appearance of amylase in the blood circulation. Under in vitro or in vivo conditions, supramaximal secretagogue stimulation resulted in (a) marked inhibition of exocytotic activity at the luminal plasma membrane, (b) the appearance of intergranule contacts and fusions within the cytoplasm, and (c) the appearance of exocytotic activity at the lateral plasma membrane. Lateral exocytotic images were observed with individual and fused zymogen granules and autophagic vacuoles. This redirection in the final step of the secretory pathway provides in part the biological basis for the increased appearance of pancreatic (pro)enzymes in the interstitial fluid and serum during supramaximal secretagogue stimulation.