The release of neurotransmitters by Ca²⁺-triggered synaptic vesicle exocytosis is an exquisitely regulated process that is fundamental for interneuronal communication. This process involves several steps and is controlled by a protein machinery that must prevent release before Ca²⁺ entry into presynaptic terminals, and yet must rapidly induce release on Ca²⁺ influx. Extensive studies of the components of this machinery have indicated that SNAREs and Munc18-1 are central proteins for membrane fusion during exocytosis. An increasing amount of information derived from a convergence of structural, physiological and genetic studies is providing important insights into the mechanism of neurotransmitter release.