Despite advances in nonpharmacologic and pharmacologic therapy, blood pressure control rates in hypertension are low. About 10 % of patients with hypertension fulfill the criteria of therapy resistance, which is defined as noncontrolled blood pressure despite treatment with ≥3 antihypertensive drugs of different classes, including a diuretic, at optimal or maximal tolerated doses. Although the pathogenesis of resistant hypertension is multifactorial, an interaction between renal afferent and efferent sympathetic nerves and the central nervous system plays a key role, leading to increased renal and central sympathetic activity. Catheter-based renal sympathetic denervation (RDN) is a novel therapeutic technique for the treatment of resistant hypertension. Clinical trials of RDN have shown a significant and sustained reduction of blood pressure as well as renal and central sympathetic activity. In clinical practice, appropriate patient selection is crucial to ensure successful and safe treatment. Beyond hypertension, RDN was associated with reduction of heart rate, regression of left ventricular mass, and improvements in glucose metabolism and severity of sleep apnea. Further studies addressing open questions in the treatment of resistant hypertension and evaluating potential new indications such as metabolic syndrome or heart failure (RE-ADAPT-HF) are necessary to prove effectiveness and safety of RDN in these patients. By modulating sympathetic activity, RDN has the potential to provide benefit in a variety of diseases, but these concepts have to be evaluated in well-designed prospective controlled clinical trials.