The mounting epidemic of overweight and obesity has made understanding the relationship between excess weight and associated comorbidities more urgent. Obesity is one of the strongest predictors of the development of hypertension and is an independent risk factor for cardiovascular disease, renal disease, and diabetes mellitus. The concomitant presence of obesity and hypertension, as commonly occurs in the cardiometabolic syndrome, magnifies the risk for cardiovascular and renal disease. The term “obesity—hypertension” thus serves to underscore the link between these two deleterious conditions and to emphasize the imperative for clinical intervention. Adipose tissue is now known to produce hormones and cytokines that promote inflammation, lipid accumulation, and insulin resistance. In addition, adipose tissue contains all the components of the renin—angiotensin system (RAS), which is upregulated in the presence of obesity. Evidence implicates activation of the systemic and adipose tissue RAS, as well as the sympathetic nervous system, as key obesity-related mechanisms of hypertension and other components of the cardiometabolic syndrome. RAS blockade therefore becomes a potential therapeutic strategy in patients with obesity-related hypertension and in persons with the cardiometabolic syndrome. Clinical trials of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers conducted in predominantly overweight/obese populations have demonstrated significant reductions in cardiovascular and renal disease risk among a range of at-risk patients. RAS blockade also is associated with a reduced risk of new-onset diabetes compared with other classes of antihypertensive therapy. Randomized, controlled trials conducted specifically in patients with obesity and hypertension are needed to determine the optimal therapeutic approach for these patients.