Renal denervation (RDN) is a safe and effective strategy for the treatment of difficult to treat hypertension. The blood pressure (BP)-lowering efficacy of RDN is comparable to those of many single antihypertensive medications and it allows to consider the RDN as a valuable option for the treatment of difficult to treat hypertension together with lifestyle modifications and medical therapy. A multidisciplinary team is of pivotal importance from the selection of the patient candidate for the procedure to the post-procedural management. Further studies are needed to investigate the effect of RDN on clinical outcomes and to better identify the predictors of BP response to RDN in order to recognize the patients who are more likely to benefit from the procedure.