Sympathetic nervous system (SNS) plays a major role in the pathogenesis of hypertension. The activity of SNS is particularly abnormal in resistant hypertension. It is firmly established that neurogenic factors mediate the onset and progression of hypertension. The link between the kidney and the brain has the anatomic basis via renal afferent and efferent nerves, correlating with excessive SNS activity in all grades of hypertension. This pathophysiological connection between the kidney and brain is confirmed by enhanced muscle sympathetic nerve activity and non-epinephrine spill over in human hypertension. The results of RDN therapy in hypertension suggest a reduction in the SNS activity and renal nerve traffic. The pathophysiologic mechanisms discussed explain the physiological rationale for renal denervation therapy in hypertension. While the gross therapeutic consequences of renal denervation on the mechanisms of hypertension are evident, the molecular and cellular correlates of such mechanisms remain to be elucidated.