Although numerous electrophysiological and biochemical studies have defined many of the properties of the putative Ca2+ receptor for exocytosis at the synapse, the molecular mechanisms that couple influx of Ca2+ and release of neurotransmitter have remained elusive. Several proteins have emerged recently as putative Ca2+ sensors. Interestingly, one of these proteins, synaptotagmin, shares many properties with the putative Ca2+ receptor. Recent genetic experiments in Caenorhabditis elegans, Drosophila and mouse have provided important insights about synaptotagmin's role in neurotransmitter release. These experiments, combined with electrophysiological and biochemical studies, suggest that synaptotagmin is a key Ca2+ sensor, converting the ubiquitously used cellular secretory pathway into a Ca(2+)-regulated exocytotic pathway.