This review describes the development of the molecular level Ca(2+)-voltage hypothesis. Theoretical considerations and feedback between theory and experiments played a key role in its development. The theory, backed by experiments, states that at fast synapses, membrane potential by means of presynaptic inhibitory autoreceptors controls initiation and termination of neurotransmitter release. A molecular kinetic scheme which depicts initiation and termination of evoked release is discussed. This scheme is able to account for both spontaneous release and evoked release. The physiological implications of this scheme are enumerated.