The discovery of cannabinoid receptors led to the development of several compounds targeted against these receptors. In particular, CB1 receptor antagonists have been described to possess key functions in the treatment of obesity and obesity-related pathologies. Numerous clinical trials revealed the advantage of strategies designed to block CB1 receptor but also evidenced the limitations due to side effects exerted by these substances. Recent studies have highlighted that CB1 antagonists could have other effects and find applications even in other pathologies like hepatic fibrosis, chronic inflammatory conditions, diabetes, and cancer. Since the suspending sales of the lead compound, rimonabant, and the discontinuation of all ongoing clinical trials of CB1 blockers, alternative strategies could emerge and lead to the development of further basic research studies to redirect these compounds.