Renal sympathetic denervation (RSD) was introduced as a promising technique for the treatment of patients with true drug-resistant hypertension. Increased sympathetic firing has been considered a pivotal pathophysiological mechanism underlying adverse cardiovascular adaptations and metabolic derangements. The cause–effect relationship between metabolic disease and sympathetic overactivity has not been fully understood. It has been hypothesized that reduction of efferent sympathetic drive might be associated with beneficial effects on metabolic surrogates and especially on insulin resistance beyond blood pressure lowering. The limited evidence so far qualifies RSD as a potential ‘upstream’ therapy to ameliorate insulin resistance. However, the impact of RSD on metabolic syndrome components, especially of obesity, is less clear and biologically questioned. In addition, sleep apnea strongly associated with resistant hypertension and glucose metabolism impairment might constitute an additional target of RSD, as sympathetic activation is highly pronounced in this setting. At present, RSD should not be considered a clinical option to treat metabolic disease, but only as an innovative technique requiring strong evidence in the field.