Recent studies suggest that endocannabinoids act as retrograde messengers at many synapses in the central nervous system. Activation of phospholipases, either through calcium-mediated or receptor-mediated signaling, leads to the formation and release of endocannabinoids. These lipophilic signaling molecules diffuse to nearby presynaptic terminals where they bind to specific G-protein-coupled receptors and inhibit neurotransmitter release for tens of seconds. Thus, an important physiological role of endocannabinoids may be to provide a mechanism by which neurons can rapidly regulate the strength of their synaptic inputs.