Metabolic bariatric surgery (MBS) is the most effective long-term treatment for common (severe) obesity in adults. It promotes substantial weight loss and improvement of obesity-related conditions such as type 2 diabetes. However, outcomes in patients with genetically confirmed obesity differ based on the underlying gene defect. In syndromic obesity, such as Prader-Willi and Bardet-Biedl syndromes, MBS typically results in limited and less sustained weight loss, with potential risks outweighing the benefits. Lifestyle interventions and medication are often preferred as first-line treatments. In monogenic non-syndromic obesity, especially in patients with monoallelic MC4R variants, Roux-en-Y gastric bypass (RYGB) can lead to short-term weight loss similar to controls, though long-term weight maintenance remains a challenge. For patients with rare biallelic variants, such as in MC4R or LEPR, MBS shows limited effectiveness. Emerging pharmacological therapies targeting specific genetic pathways, such as melanocortin receptor agonists, may offer promising (long-term) solutions and should be considered as part of a personalized, combined treatment strategy.