In pancreatic B- and A-cells, metabolic stimuli regulate biochemical and electrical processes that culminate in Ca2+-influx and release of insulin or glucagon, respectively. Like in other (neuro)endocrine cells, Ca2+-influx triggers the rapid exocytosis of hormone-containing secretory granules. Only a small fraction of granules (<1% in insulin-secreting B-cells) can be released immediately, while the remainder requires translocation to the plasma membrane and further "priming" for release by several ATP- and Ca2+-dependent reactions. Such functional organization may account for systemic features such as the biphasic time course of glucose-stimulated insulin secretion. Since this release pattern is altered in type-2 diabetes mellitus, it is conceivable that disturbances in the exocytotic machinery underlie the disease. Here I will review recent data from our laboratory relevant for the understanding of these processes in insulin-secreting B-cells and glucagon-secreting A-cells and for the identification of novel targets for antidiabetic drug action. Two aspects are discussed in detail: 1) The importance of a tight interaction between L-type Ca2+-channels and the exocytotic machinery for efficient secretion; and 2) the role of intragranular acidification for the priming of secretory granules and its regulation by a granular 65-kDa sulfonylurea-binding protein.