A role for phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) in membrane fusion was originally identified for regulated dense-core vesicle exocytosis in neuroendocrine cells. Subsequent studies demonstrated essential roles for PI(4,5)P(2) in regulated synaptic vesicle and constitutive vesicle exocytosis. For regulated dense-core vesicle exocytosis, PI(4,5)P(2) appears to be primarily required for priming, a stage in vesicle exocytosis that follows vesicle docking and precedes Ca(2) (+)-triggered fusion. The priming step involves the organization of SNARE protein complexes for fusion. A central issue concerns the mechanisms by which PI(4,5)P(2) exerts an essential role in membrane fusion events at the plasma membrane. The observed microdomains of PI(4,5)P(2) in the plasma membrane of neuroendocrine cells at fusion sites has suggested possible direct effects of the phosphoinositide on membrane curvature and tension. More likely, PI(4,5)P(2) functions in vesicle exocytosis as in other cellular processes to recruit and activate PI(4,5)P(2)-binding proteins. CAPS and Munc13 proteins, which bind PI(4,5)P(2) and function in vesicle priming to organize SNARE proteins, are key candidates as effectors for the role of PI(4,5)P(2) in vesicle priming. Consistent with roles prior to fusion that affect SNARE function, subunits of the exocyst tethering complex involved in constitutive vesicle exocytosis also bind PI(4,5)P(2). Additional roles for PI(4,5)P(2) in fusion pore dilation have been described, which may involve other PI(4,5)P(2)-binding proteins such as synaptotagmin. Lastly, the SNARE proteins that mediate exocytic vesicle fusion contain highly basic membrane-proximal domains that interact with acidic phospholipids that likely affect their function.