Purpose of review <p>This review aims to synthesize current evidence on the magnitude, timing, and determinants of weight relapse following discontinuation of incretin-based anti-obesity therapies and critically evaluates emerging strategies to mitigate post-treatment weight rebound.</p> Recent findings <p>Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 receptor agonists, represent the most effective pharmacologic options currently available for weight management. While existing studies have predominantly focused on short-to-intermediate-term safety and efficacy, comparatively little attention has been paid to outcomes following treatment discontinuation. Emerging evidence from randomized trials, extension studies, and real-world cohorts consistently demonstrates substantial and clinically meaningful weight relapse after therapy withdrawal.</p> Summary <p>Obesity is a chronic, relapsing disease that requires long-term management and monitoring to achieve durable therapeutic benefit and prevent relapse. Incretin-based agents exert pleiotropic effects that modulate central appetite, gastric emptying, and gut–brain hormonal influence. Discontinuation is associated with reversal of these mechanisms, leading to increased appetite, metabolic dysregulation, hormonal re-adaptation, and the re-emergence of behavioral, psychological, and environmental drivers of weight gain. Genetic and epigenetic factors, comorbidities, and lifestyle influence further modulate individual susceptibility to post-treatment weight relapse. At present, however, there are no definitive guidelines regarding optimal treatment duration, withdrawal strategies, or validated biomarkers to predict relapse risk. By framing incretin therapy within the paradigm of chronic, relapsing obesity, guideline-driven, risk-stratified long-term management approaches are necessary to preserve weight change and sustain cardiometabolic benefits after treatment withdrawal.</p>