There are at least 2 types of cannabinoid receptor, CB₁ and CB₂, both G protein coupled. CB₁ receptors are expressed predominantly at nerve terminals and mediate inhibition of transmitter release, whereas CB₂ receptors are found mainly on immune cells, their roles including the modulation of cytokine release and of immune cell migration. Endogenous agonists for cannabinoid receptors also exist. These “endocannabinoids” are synthesized on demand and removed from their sites of action by cellular uptake and intracellular enzymic hydrolysis. Endocannabinoids and their receptors together constitute the endocannabinoid system. This review summarizes evidence that there are certain central and peripheral disorders in which increases take place in the release of endocannabinoids onto their receptors and/or in the density or coupling efficiency of these receptors and that this upregulation is protective in some disorders but can have undesirable consequences in others. It also considers therapeutic strategies by which this upregulation might be modulated to clinical advantage. These strategies include the administration of (1) a CB₁ and/or CB₂ receptor agonist or antagonist that does or does not readily cross the blood brain barrier; (2) a CB₁ and/or CB₂ receptor agonist intrathecally or directly to some other site outside the brain; (3) a partial CB₁ and/or CB₂ receptor agonist rather than a full agonist; (4) a CB₁ and/or CB₂ receptor agonist together with a noncannabinoid, for example, morphine or codeine; (5) an inhibitor or activator of endocannabinoid biosynthesis, cellular uptake, or metabolism; (6) an allosteric modulator of the CB₁ receptor; and (7) a CB₂ receptor inverse agonist.