Δ⁹-Tetrahydrocannabinol from Cannabis sativa is mimicked by cannabimimetic analogs such as CP55940 and WIN55212-2, and antagonized by rimonabant and SR144528, through G-protein-coupled receptors, CB₁ in the brain, and CB₂ in the immune system. Eicosanoids anandamide and 2-arachidonoylglycerol are the “endocannabinoid” agonists for these receptors. CB₁ receptors are abundant in basal ganglia, hippocampus and cerebellum, and their functional activity can be mapped during behaviors using cerebral metabolism as the neuroimaging tool. CB₁ receptors couple to G_i/o to inhibit cAMP production, decrease Ca²⁺ conductance, increase K⁺ conductance, and increase mitogen-activated protein kinase activity. Functional activation of G-proteins can be imaged by [35S]GTPγS autoradiography. Post-synaptically generated endocannabinoids form the basis of a retrograde signaling mechanism referred to as depolarization-induced suppression of inhibition (DSI) or excitation (DSE). Under circumstances of sufficient intracellular Ca²⁺ (e.g., burst activity in seizures), synthesis of endocannabinoids releases a diffusible retrograde messenger to stimulate presynaptic CB₁ receptors. This results in suppression of γ-aminobutyric acid (GABA) release, thereby relieving the post-synaptic inhibition. Tolerance develops as neurons adjust both receptor number and cellular signal transduction to the chronic administration of cannabinoid drugs. Future therapeutic drug design can progress based upon our current understanding of the physiology and pharmacology of CB₁, CB₂ and related receptors. One very important role for CB₁ antagonists will be in the treatment of craving in the disease of substance abuse.