Acinar cells are one of the best studied models of exocytotic secretion. A number of different hormones and neurotransmitters interact with specific membrane receptors, and it is commonly held that pancreatic secretagogues stimulate enzyme release via the elevation of either cytosolic free Ca2+ or cellular cyclic adenosine monophosphate. The discovery of the pivotal role played by phospholipid metabolism in the chain of events leading to secretion, together with the introduction of sensitive techniques to monitor cytosolic free Ca2+, has generated a series of studies that have challenged this classical model. Thus, several observations in pancreatic acini as well as other cell types have argued against the notion that a generalized increase in cytosolic free Ca2+ represents a sufficient and necessary stimulus for exocytosis in nonexcitable cells. Furthermore, the demonstration that a single agonist activates multiple transduction pathways has served to refute the schematic view that receptor agonists activate only one second messenger system. The aim of this article is to review the recent advances in understanding the molecular and cellular mechanisms of signal transduction, with particular emphasis on the inositol lipid pathway, and to integrate this information into a new working model of enzyme secretion from acinar cells.