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The ECS comprises a set of molecular components, including enzymes, signalling lipids and G\u2010protein coupled receptors, which has an outstanding role in modulating eating behaviour and energy homeostasis. Interestingly, evidence has shown that the ECS is present at the central and peripheral nervous system, modulating the function of the hypothalamus, the brain reward system and the brainstem, and coordinating the crosstalk between these brain structures and peripheral organs. Indeed, the ECS is present and functional in metabolically relevant peripheral tissues, directly modulating their physiology. In the context of a global obesity pandemic, these discoveries are highly suggestive in order to design novel pharmaceutical tools to fight obesity and related morbidities. In fact, a cannabinoid\u2010based first generation of drugs was developed and marketed. Their failure, due to central side\u2010effects, is leading to a second generation of these drugs unable to cross the blood\u2013brain barrier, as well as other ECS\u2010focused strategies that are still in the pipeline. In the next few years we will hopefully know whether such an important player in energy homeostasis can be successfully targeted without significantly affecting other vital processes related to mood and sense of well\u2010being. 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