Hypertension is a frequent comorbidity of obesity that significantly and independently increases the risk of cardiovascular and renal events. Obesity-related hypertension is a major challenge to the healthcare system because of the rapid increase in obesity prevalence worldwide. However, its treatment is still not specifically addressed by current guidelines. Weight loss (WL)reduces blood pressure (BP) and increases patient responsiveness to BP-lowering medications. Thus, a weight-centric approach is essential for the treatment of obesity-related hypertension. Diet and physical activity are key components of lifestyle interventions for obesity-related hypertension, but, in real life, their efficacy is limited by poor long-term patient adherence and frequently require pharmacotherapy implementation to achieve target BP. In this context, first-generation anti-obesity drugs such as orlistat, phentermine/topiramate, and naltrexone/bupropion are poorly effective, whereas second-generation incretin receptor agonists, including the GLP-1 receptor agonists liraglutide and semaglutide, and in particular the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) co-agonist tirzepatide, substantially contribute to effective WL and BP control in obesity. SGLT2 inhibitors are weak body weight and BP-lowering medications, but clearly synergize the benefits of these medications. Bariatric surgery remains the gold standard treatment for severe "pathological" obesity and related life-threatening complications. Renal denervation is a valuable rescue treatment for drug-resistant hypertension, commonly related to obesity. Integrating a multifaceted weight-based approach with other strategies, such as antihypertensive drugs and renal denervation, could specifically target the main neuro-hormonal and renal pathophysiological mechanisms of obesity-related hypertension, including sympathetic-nervous and renin-angiotensin-aldosterone systems overactivity, salt retention, and volume expansion. This comprehensive strategy can provide a personalized algorithm for managing hypertension in obesity within the context of "precision medicine" principles.