Resistant hypertension remains a major clinical problem despite the available multidrug therapy. Over the next decades, its incidence will likely increase given that it is strongly associated with older age and obesity. Resistant hypertension patients have an increased cardiovascular risk, thus effective antihypertensive treatment will provide substantial health benefits. The crosstalk between sympathetic nervous system and kidneys plays a crucial role in hypertension. It influences several pathophysiological mechanisms such as the central sympathetic tone, the sodium balance and the systemic neurohumoral activation. In fact, studies using several animal models demonstrated that the renal denervation prevented and attenuated hypertension in multiple species. Large reductions in blood pressure were also observed in malignant hypertension patients submitted to sympathectomy surgeries. However, these approaches had an unacceptably high rates of periprocedural complications and disabling adverse events. Recently, an innovative non-pharmacological therapy that modulates sympathetic activation has been successfully developed. Renal sympathetic percutaneous denervation is an endovascular procedure that uses radiofrequency energy to destroy the autonomic renal nerves running inside the adventitia of renal arteries. This method represents a promising new approach to the strategy of inhibiting the sympathetic nervous system. The aim of this review is to examine the background knowledge that resulted in the development of this hypertension treatment and to critically appraise the available clinical evidence.