Abundant evidence shows that chronic kidney disease (CKD) is a disease state characterized by increased sympathetic activation. Kidney injury (ischemia) plays a central role in this pathogenesis. Sympathetic excitation is associated with an increased risk of cardiovascular morbidity and mortality. Several pharmacologic strategies are developed to decrease sympathetic activity. However, these medications have limitations. Percutaneous catheter-based renal denervation has the potential to become a new treatment option for CKD. This current report focuses on the effects of sympathetic hyperactivity in CKD, and gives an overview in experimental as well as clinical evidence for a central role of the kidneys in the pathophysiology of sympathetic hyperactivity. Moreover, the effect of pharmacologic treatment and the potential beneficial effect of renal denervation will be discussed.