Activation of presynaptic receptors for a variety of neurotransmitters and neuromodulators inhibits transmitter release at many synapses. Such presynaptic inhibition might serve as a means of adjusting synaptic strength or preventing excessive transmitter release, or both. Previous evidence showed that presynaptic modulators inhibit Ca2+ channels and activate K+ channels at neuronal somata. These modulators also inhibit spontaneous transmitter release by mechanisms downstream of Ca2+ entry. The relative contribution of the above mechanisms to the inhibition of elicited release has been debated for a long time. Recent evidence at synapses where the relationship between transmitter release and presynaptic Ca2+ influx has been well characterized suggests that inhibition of presynaptic voltage-dependent Ca2+ channels plays the major role in presynaptic inhibition of elicited neurotransmitter release. In addition, modulation of the release machinery might contribute to inhibition of elicited release.