Cannabinoid receptors are the molecular targets for the active component Delta(9)-tetrahydrocannabinol of marijuana and hashish, and constitute a major family of G protein-coupled seven-transmembrane-domain receptors. They consist of type 1 (CB1) and type 2 (CB2) receptors of which the CB1 is rich in various regions of the CNS. Accumulated evidence suggests that endogenous cannabinoids function as diffusible and short-lived intercellular messengers that modulate synaptic transmission. Recent studies have provided strong experimental evidence that endogenous cannabinoids mediate signals retrogradely from depolarized postsynaptic neurons to presynaptic terminals to suppress subsequent neurotransmitter release, driving the synapse into an altered state. In hippocampal neurons, depolarization of postsynaptic neurons and resultant elevation of [Ca(2+)](i) lead to transient suppression of inhibitory transmitter release (depolarization-induced suppression of inhibition, DSI). In cerebellar Purkinje cells, on the other hand, depolarization-induced elevation of [Ca(2+)](i) causes transient suppression of excitatory transmitter release (depolarization-induced suppression of excitation, DSE). DSI and DSE appear to share the same properties and may be a general and important mechanism by which the postsynaptic neuronal activity can influence the amount of transmitter release.