Resistant hypertension, defined as failure to reach blood pressure (BP) goals despite treatment with ≥3 antihypertensive agents, one of which is a diuretic, bears a significant risk of cardiovascular complications. Strong evidence exists, implicating the overactivation of the sympathetic nervous system (SNS) in the pathogenesis of resistant hypertension through complex neurohormonal interactions. Renal denervation is a novel attractive option to achieve adequate blockade of the sympathetic system, with subsequent BP reductions in patients with resistant hypertension. Data have shown promising results regarding the efficacy of the procedure, maintaining a favorable safety profile. As such, the paradigm of resistant hypertension has expanded in other conditions involving a hyperadrenergic state such as the metabolic syndrome, heart failure, arrhythmias, sleep apnea, and renal failure. This review focuses on the pathophysiological rationale of modifying SNS tone and the evidence of the benefits of such intervention beyond BP control.