While postsynaptic ionotropic and metabotropic glutamate receptors have received the lions share of attention in studies of long-term activity-dependent synaptic plasticity, it is becoming clear that presynaptic metabotropic glutamate receptors play critical roles in both short-term and long-term plasticity of vesicular transmitter release, and that they act both at the level of voltage-dependent calcium channels and directly on proteins of the vesicular release machinery. Activation of G protein-coupled receptors can transiently inhibit vesicular release through the release of G?? which binds to both voltage-dependent calcium channels to reduce calcium influx, and directly to the C-terminus region of the SNARE protein SNAP-25. Our recent work has revealed that the binding of G?? to SNAP-25 is necessary, but not sufficient, to elicit long-term depression (LTD) of vesicular glutamate release, and that the concomitant release of G?(i) and the second messenger nitric oxide are also necessary steps in the presynaptic LTD cascade. Here, we review the current state of knowledge of the molecular steps mediating short-term and long-term plasticity of vesicular release at glutamatergic synapses, and the many gaps that remain to be addressed. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.