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Cannabis (marijuana) is not only a frequently abused drug but also has the potential for the development of useful agents for the treatment of emesis, anorexia and multiple sclerosis. In this article, the effects of modulation of transmitter release by cannabinoids in both the CNS and the PNS of various species, including humans, will be discussed. Cannabinoids inhibit neurotransmitter release via specific presynaptic cannabinoid CB₁ receptors. Studies using either the CB₁ receptor antagonist and inverse agonist SR141716 or CB₁-receptor-deficient mice suggest that numerous presynaptic cannabinoid receptors are tonically activated by endogenous cannabinoids and/or are constitutively active. CB₁-receptor-mediated inhibition of transmitter release might explain, for example, reinforcing properties and memory impairment caused by cannabinoids.