Transmitter release is a fast Ca(2+)-dependent process triggered in response to membrane depolarization. It involves two major calcium-binding proteins, the voltage-gated calcium channel (VGCC) and the vesicular protein synaptotagmin (syt1). Ca(2+) binding triggers transmitter release with a time response of conformational changes that are too fast to be accounted for by Ca(2+) binding to syt1. In contrast, conformation-triggered release, which engages Ca(2+) binding to VGCC, better accounts for the fast rate of the release process. Here, we summarize findings obtained from heterologous expression systems, neuroendocrine cells, and reconstituted systems, which reveal the molecular mechanism by which Ca(2+) binding to VGCC triggers exocytosis prior to Ca(2+) entry into the cell. This review highlights the molecular aspects of an intramembrane signaling mechanism in which a signal is propagated from the channel transmembrane (TM) domain to the TM domain of syntaxin 1A to trigger transmitter release. It discusses fundamental problems of triggering transmitter release by syt1 and suggests a classification of docked vesicles that might explain synchronous transmitter release, spontaneous release, and facilitation of transmitter release.