This chapter describes the role of the endocannabinoid system (ECBS) in processes associated with cocaine addiction and relapse. Modification of the ECBS activity by blockade of cannabinoid type 1 receptors (CB1R) as well as by fatty acid amide hydrolase inhibitors does not affect cocaine self-administration but potently attenuates the reinstatement of cocaine- and cue-induced seeking behavior, the procedure believed to simulate cocaine craving and relapse in humans. These data are consistent with findings showing that several other behavioral effects of cocaine are inhibited or reversed by ligands of cannabinoid receptors. Repeated cocaine administration also causes upregulation of the CB1Rs in a number of brain areas known to be involved in motivational and cognitive processes associated with cocaine addiction. We conclude that CB1Rs are directly involved in pharmacological and motivational aspects of cocaine addiction, and therefore, can be a potential target for development of new and effective treatment of cocaine abuse and dependence.