Blockade of the CB(1) receptor is one of the promising strategies for the treatment of obesity. The first selective CB(1) receptor antagonist, rimonabant, which has already successfully completed phase III clinical trials, led to sustained weight loss and a reduction in waist circumference. Patients treated with rimonabant also demonstrated statistically significant improvement in high-density lipoprotein cholesterol levels, triglyceride levels and insulin resistance, as well as a reduced overall prevalence of metabolic syndrome. Currently, one of the most discussed aspects of endocannabinoid system function is to what extent the endocannabinoid system might affect metabolism independently of its control over body weight and food intake. Specifically, a food-intake- and body-weight-independent role in the regulation of glucose homeostasis and insulin sensitivity could have major impact on the potential of drug candidates targeting the endocannabinoid system for the prevention and treatment of metabolic syndrome. This review summarises the effects of the endocannabinoid system on glucose homeostasis and insulin sensitivity.