Resistant hypertension, defined as inadequate blood pressure control despite three or more antihypertensive medications at maximally tolerated doses, is strongly linked to increased cardiovascular morbidity and mortality. Increased renal afferent and efferent sympathetic activity carried by nerves which arborize the adventitia of the renal arteries, appears to be central to the pathobiology of resistant hypertension. Historical experience indicates that surgical denervation and/or sympathectomy often dramatically reduced blood pressure in patients with malignant hypertension. Catheter-based radio-frequency renal denervation was developed in the past decade as a percutaneous adaptation of surgical denervation. Percutaneous renal denervation using a variety of systems has demonstrated to date, in non-randomized and unblinded studies, dramatic reductions in office-based blood pressure, but more modest impact on ambulatory blood pressure. The only single, appropriately powered, blinded, sham-controlled study of renal denervation conducted to date, however, failed to meet its primary endpoint, casting doubt on the value of the therapy. Ancillary benefits of renal denervation have been described in such conditions as diabetes mellitus, heart failure, and sleep apnea but require further study. While renal denervation is already widely available outside of the USA for commercial use, its utility in resistant hypertension must be vetted by further rigorous investigation before its use can be routinely recommended.