Despite the availability of safe and effective antihypertensive drugs, blood pressure (BP) control to guideline-recommended target values is poor. Several device-based therapies have been introduced to lower BP. The most extensively investigated approach is catheter-based renal sympathetic denervation (RDN), which aims to interrupt the activity of afferent and efferent renal sympathetic nerves by applying radiofrequency energy, ultrasound energy, or injection of alcohol in the perivascular space. The second generation of placebo-controlled trials have provided solid evidence for the BP-lowering efficacy of radiofrequency- and ultrasound-based RDN in patients with and without concomitant pharmacological therapy. In addition, the safety profile of RDN appears to be excellent in all registries and clinical trials. However, there remain unsolved issues to be addressed. This review summarizes the rationale as well as the current evidence and discusses open questions and possible future indications of catheter-based RDN.