The presence in the mammalian brain of specific receptors for marijuana triggered a search for endogenous ligands, several of which have been recently identified. There has been growing interest in the possible physiological functions of endocannabinoids, and mutant mice that lack cannabinoid receptors have become an important tool in the search for such functions. To date, studies using CB1 knockout mice have supported the possible role of endocannabinoids in retrograde synaptic inhibition in the hippocampus, in long-term potentiation and memory, in the development of opiate dependence, and in the control of appetite and food intake. They also suggested the existence of as yet unidentified cannabinoid receptors in the cardiovascular and central nervous systems. The use of CB2 receptor knockout mice suggested a role for this receptor in macrophage-mediated helper T cell activation. Further studies will undoubtedly reveal many additional roles for this novel signaling system.