Hypertension remains a major public health problem and one of the most relevant causes of cardiovascular mortality and morbidity worldwide. Roughly 10% of hypertensive individuals are considered as “resistant” as they are not able to achieve and maintain optimal blood pressure values despite the concurrent use of 3 antihypertensive agents of different classes at optimal doses. As resistant hypertension conveys a higher risk of adverse outcomes, the search for effective treatments to properly manage this condition has progressively surged as a true health priority. The renal nerve plexus plays a central role in regulating arterial blood pressure and renal sympathetic overactivity is a major component in the development and progression of hypertension. On these premises, minimally-invasive catheter based devices for renal nerve ablation have been developed and tested as an alternative treatment for resistant hypertension, but clinical study results have been ambiguous. This review provides a historical perspective on the scientific evidence forming the foundation of renal never ablation from accrued clinical evidence to possible future applications, reaching a tentative conclusion that more research and clinical experience is needed to fully reveal limits and potential indications of this procedure.