Milestones in the journey towards addressing obesity; Past trials and triumphs, recent breakthroughs, and an exciting future in the era of emerging effective medical therapies and integration of effective medical therapies with metabolic surgery.

The 21st century is characterized by an increasing incidence and prevalence of obesity and the burden of its associated comorbidities, especially cardiometabolic diseases, which are reaching pandemic proportions. In the late '90s, the "black box" of adipose tissue and energy homeostasis was opened with the discovery of leptin, transforming the adipose tissue from an "inert fat-storage organ" to the largest human endocrine organ and creating the basis on which more intensified research efforts to elucidate the pathogenesis of obesity and develop novel treatments were based upon. Even though leptin was eventually not proven to be the "standalone magic bullet" for the treatment of common/polygenic obesity, it has been successful in the treatment of monogenic obesity syndromes. Additionally, it shifted the paradigm of treating obesity from a condition due to "lack of willpower" to a disease due to distinct underlying biological mechanisms for which specific pharmacotherapies would be needed in addition to lifestyle modification. Subsequently, the melanocortin pathway proved to be an equally valuable pathway for the pharmacotherapy of obesity. Melanocortin receptor agonists have recently been approved for treating certain types of syndromic obesity. Other molecules- such as incretins, implicated in energy and glucose homeostasis- are secreted by the gastrointestinal tract. Glucagon-like peptide 1 (GLP-1) is the most prominent one, with GLP-1 analogs approved for common/polygenic obesity. Unimolecular combinations with other incretins, e.g., GLP-1 with gastric inhibitory polypeptide and/or glucagon, are expected to be approved soon as more effective pharmacotherapies for obesity and its comorbidities. Unimolecular combinations with other compounds and small molecules activating the receptors of these molecules are currently under investigation as promising future pharmacotherapies. Moreover, metabolic and bariatric surgery has also demonstrated impressive results, especially in the case of morbid obesity. Consequently, this broadening therapeutic armamentarium calls for a well-thought-after and well-coordinated multidisciplinary approach, for instance, through cardiometabolic expertise centers, that would ideally address effectively and cost-effectively obesity and its comorbidities, providing tangible benefits to large segments of the population.