Prior to the emergence of percutaneous radiofrequency-based therapy for renal denervation, considerable preclinical and clinical experience reinforced the importance for afferent and efferent renal sympathetic nerve activity in the initiation and maintenance of hypertension and other cardiovascular diseases. The role of the adrenergic tone is also supported by the evidence of an increased renal norepinephrine spillover to plasma in resistant hypertensives – a biomarker of increased renal sympathetic activation. The observation that surgical renal sympathectomy improved blood pressure control has led to the considerations of a percutaneous approach to renal sympathetic denervation. The rapid evolution in our understanding of both the human renal nerve microanatomy and the ideal technique for the safe application of radiofrequency technology leads to successful renal nerve ablation in previous trials on resistant hypertension and for future studies in pathophysiological conditions characterized by an hyperadrenergic tone.