2-Arachidonoylglycerol (2-AG) is an endogenous cannabinoid (endocannabinoid) lipid whose functions remain poorly understood. Guindon and colleagues report the novel finding that exogenous application of 2-AG induces peripheral antinociceptive effects that are mediated, at least in part, by actions at peripheral cannabinoid CB2 receptors. URB602, a recently described inhibitor of monoacylglycerol lipase, an enzyme that catalyzes 2-AG hydrolysis in vivo, also induced peripheral antinociceptive effects and enhanced the actions of 2-AG. Peripheral analgesic mechanisms represent promising therapeutic targets for suppressing pain in the absence of unwanted central nervous system side-effects (e.g. psychoactivity) associated with activation of central CB1 receptors. The therapeutic potential of inhibitors of 2-AG deactivation for the treatment of inflammatory pain is discussed.