Preparations of the hemp Cannabis sativa L. were widely used for therapeutic or ritual purposes in ancient times. An important milestone was the isolation and elucidation of the structure of its main psychoactive constituent ∆9-tetrahydrocannabinol (∆9-THC) in 1964. The existence of cannabinoid receptors was confirmed in 1988, with the CB1 receptor cloned in 1990 and the CB2 receptor found by sequence homology three years later. The quest for endogenous ligands led to the discovery of anandamide (arachidonoylethanolamide) from porcine brain. The endocannabinoid system, as a signaling system, has components responsible for synthesis, action, and inactivation of endocannabinoids, all of which are legitimate targets for pharmacological intervention. This Perspective describes compounds affecting the major targets of the endocannabinoid system and outlines some of the possible therapeutic benefits of such compounds.