When compared with other modifiable cardiovascular risk factors, such as hypertension, dyslipidemia and smoking, obesity remains a surprisingly puzzling condition to prevent and treat. The history of the development of anti-obesity drugs has known more defeats than even partial victories. With very few drugs on the market, and bad publicity related to adverse events, obesity remains an almost completely unmet challenge for the pharmaceutical industry. In light of past experience with endocannabinoid-system antagonists, such as rimonabant, we propose that a major paradigm shift in clinical practice might be necessary to justify the use of pharmacotherapy for obesity. Furthermore, we suggest that the criteria currently used by regulatory authorities to evaluate and approve anti-obesity drugs should be rigorously re-examined. Finally, we discuss how pharmacological approaches that aim to counteract overactivity of the endocannabinoid system should be revisited in the future to treat visceral (intra-abdominal) obesity and its metabolic consequences.