Despite their low abundance in biological membranes, phosphoinositides are important cellular regulators. Phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] regulates both endocytosis and exocytosis, but its role in the latter process is unclear. On p. 2084, Giampietro Schiavo and co-workers report that elimination of PtdIns(4,5)P2 from the plasma membrane is required for regulated exocytosis in activated mast cells. These cells release pro-inflammatory mediators by exocytosis of pre-formed granules, a process that involves granule-plasma-membrane fusion and granule-granule fusion but no compensatory endocytosis. Using quantitative immunofluorescence, the authors show that PtdIns(4,5)P2 is present in the plasma membrane of mast cells but not their granule membranes. Upon activation of exocytosis, they report, PtdIns(4,5)P2 is transiently depleted from the plasma membrane by phosphatidylinositol-specific phospholipase C; both removal of PtdIns(4,5)P2 and production of its metabolite diacylglycerol (but not activation of Ca2+ signalling,) are required for exocytosis. The authors conclude that a cycle of PtdIns(4,5)P2 synthesis and breakdown regulates exocytosis in mast cells and speculate that a similar cycle functions in other secretory cells.