Neurotransmitter release from neurons takes place at specialized structures called synapses. Action potential-evoked exocytosis requires Ca(2+) influx through voltage-gated Ca(2+) channels. Spontaneous vesicle fusion occurs both in the absence of action potentials and without any apparent stimulus and is hence thought to be Ca(2+)-independent. However, increasing evidence shows that this form of neurotransmitter discharge can be modulated by changes in intracellular Ca(2+) concentration, suggesting that it is not truly spontaneous. This idea is supported by the fact that spontaneous release can be modulated by interfering with proteins involved in the exocytotic process. Interestingly, modulation of spontaneous discharge at the level of the release machinery is not always accompanied by corresponding modulation of action potential-evoked release, suggesting that two independent processes may underlie spontaneous and action potential-evoked exocytosis, at least at some synapses. This provides an attractive model whereby cells can modulate the two forms of neurotransmitter liberation, which often serve different physiological roles, independently of each other.