Abstract2‐Arachidonoylglycerol is an arachidonic acid‐containing monoacylglycerol isolated from the rat brain and canine gut as an endogenous ligand for the cannabinoid receptors (CB1 and CB2). 2‐Arachidonoylglycerol binds to both the CB1 receptor, abundantly expressed in the nervous system, and the CB2 receptor, mainly expressed in the immune system, with high affinity, and exhibits a variety of cannabimimetic activities. Notably, anandamide, another endogenous ligand for the cannabinoid receptors, acts as a partial agonist at these cannabinoid receptors, whereas 2‐arachidonoylglycerol acts as a full agonist. The results of structure‐activity relationship experiments strongly suggested that 2‐arachidonoylglycerol rather than anandamide is the true natural ligand for both the CB1 and the CB2 receptors. Evidence is gradually accumulating which shows that 2‐arachidonoylglycerol plays physiologically and pathophysiologically essential roles in various mammalian tissues and cells. © 2009 International Union of Biochemistry and Molecular Biology, Inc.