Modulation of neurotransmitter release by G-protein-coupled receptors (GPCRs) is a prominent presynaptic mechanism for regulation of synaptic transmission. Activation of GPCRs located at the presynaptic terminal can decrease the probability of neurotransmitter release. This presynaptic depression involves activation of Gi/o-type G-proteins that mediate different inhibitory mechanisms, including inhibition of voltage-gated calcium channels, activation of potassium channels, and direct inhibition of the vesicle fusion process. A variety of neurotransmitters and modulatory agents can activate GPCRs that produce presynaptic depression. Among these are lipid metabolites that serve as agonists for GPCRs. The discovery of endocannabinoids and their cognate receptors, including the CB1 receptor, has stimulated intense investigation into the neurophysiological roles of these lipid metabolites. It is now clear that presynaptic depression is the major physiological role for the CB1 receptor. Endocannabinoids activate this receptor mainly via a retrograde signaling process in which these compounds are synthesized in and released from postsynaptic neuronal elements, and travel back to the presynaptic terminal to act on the CB1 receptor. This retrograde endocannabinoid modulation has been implicated in short-term synaptic depression, including suppression of excitatory or inhibitory transmission induced by postsynaptic depolarization and transient synaptic depression induced by activation of postsynaptic GPCRs during agonist treatment or synaptic activation. Endocannabinoids and the CB1 receptor also play a key role in one form of long-term synaptic depression (LTD) that involves a longlasting decrease in neurotransmitter release.