Ca -dependent secretion is a process by which important signaling molecules that are produced within a cell-including proteins and neurotransmitters-are expelled to the extracellular environment. The cellular mechanism that underlies secretion is referred to as exocytosis. Many years of work have revealed that exocytosis in neurons and neuroendocrine cells is tightly coupled to Ca and orchestrated by a series of protein-protein/protein-lipid interactions. Here, we highlight landmark discoveries that have informed our current understanding of the process. We focus principally on reductionist studies performed using powerful model secretory systems and cell-free reconstitution assays. In recent years, molecular cloning and genetics have implicated the involvement of a sizeable number of proteins in exocytosis. We expect reductionist approaches will be central to attempts to resolve their roles. The will continue to be an outlet for much of this work, befitting its tradition of publishing strongly mechanistic, basic research.