During an action potential, Ca²⁺ entering a presynaptic terminal triggers synaptic vesicle exocytosis and neurotransmitter release in less than a millisecond. How does Ca²⁺ stimulate release so rapidly and precisely? Work over the last decades revealed that Ca²⁺ binding to synaptotagmin triggers release by stimulating synaptotagmin binding to a core fusion machinery composed of SNARE and SM proteins that mediates membrane fusion during exocytosis. Complexin adaptor proteins assist synaptotagmin by activating and clamping this core fusion machinery. Synaptic vesicles containing synaptotagmin are positioned at the active zone, the site of vesicle fusion, by a protein complex containing RIM proteins. RIM proteins activate docking and priming of synaptic vesicles and simultaneously recruit Ca²⁺ channels to active zones, thereby connecting in a single complex primed synaptic vesicles to Ca²⁺ channels. This architecture allows direct flow of Ca²⁺ ions from Ca²⁺ channels to synaptotagmin, which then triggers fusion, thus mediating tight millisecond coupling of an action potential to neurotransmitter release.