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In recent years, abnormal regulation of the endocannabinoid system (ECS) has been proposed as a key factor in the development of obesity-related metabolic disorders such as diabetes. Indeed, this signaling system which includes the cannabinoid type 1 and 2 receptors (CB1R and CB2R) and their endogenous lipid ligands, has been shown to influence feeding behavior, energy expenditure, as well as glucose and lipid metabolism. Importantly, blocking CB1R function has been demonstrated to counteract metabolic aberrations associated with obesity in various murine models and in humans. Here we provide an update on recent findings describing the role of the ECS in energy balance and metabolism, and explore how recent experimental and clinical studies have delivered new insights into the therapeutic potential of this physiological system as a means of treating obesity-induced metabolic disorders.WIREs Membr Transp Signal 2013, 2:49–63. doi: 10.1002/wmts.79For further resources related to this article, please visit the WIREs website.