Introduction: Hypertension and obesity are important health challenges that independently increase cardiovascular morbidity and mortality. There is a lack of randomized controlled trials to clearly inform on preferred drug choices to be adopted in clinical practice for the treatment of obesity-related hypertension (OHT). Adequate differentiation of drug classes for preferential use in obesity or the metabolic syndrome aimed at avoiding adverse effects on body weight and the metabolic profile is neglected in this population, at least in part due to the lack of specific pharmacologic recommendations in hypertension guidelines. Areas covered: The authors summarize and suggest pharmacotherapeutic strategies based on pathophysiologic rationale to achieve blood pressure (BP) control and avoid adverse metabolic consequences in OHT. Expert opinion: Combinations of various pharmacologic antihypertensive approaches are required in the management of OHT. It is recommended that targeting sympathetic overactivity with a centrally acting sympatholytic agent such as moxonidine should be considered as a preferred second line treatment choice in combination with renin angiotensin system (RAS) blockade, the current first line choice. Though not all obese subjects have sympathetic overdrive, this approach is likely to provide effective control of blood pressure and improve the metabolic profile of patients with OHT along with positive implications for cardiovascular risk reduction.