The regulatory role of the endocannabinoid system has been implicated in many physiological and pathological functions and as a consequence the modulation of function of this system has become a therapeutic target in various diseases and pathological states. The authors give an overview of the pharmacological background of the endocannabinoid system and a short summary of the most important preclinical data. The connection between the endocannabinoid system and cardiometabolic risk is also discussed. Finally, landmark human studies with the cannabinoid antagonist rimonabant – such as the RIO, SERENADE, ARPEGGIO, STRADIVARIUS and ADAGIO-LIPIDS studies – are also reviewed.