OBJECTIVE The relationship between excessive sympathetic drive to the kidneys and hypertension is now well established. This has led to the development of therapeutic approaches, such as catheter-based bilateral renal denervation, for the treatment of resistant hypertension. The purpose of this article is to review the sympathetic regulation of kidney function, with specific focus given to clinical insights gained from human studies involving renal denervation and animal studies that have identified possible causal factors associated with disease. RESULTS Continuous chronic determinations of renal sympathetic nerve activity (RSNA) in animal models have recently identified a role of angiotensin II and obesity in the initiation of neurally related hypertension. Other potential mediating factors influencing RSNA include adipose tissue derived factors, neurohumoral pathways and baroreceptor-mediated mechanisms. Hypertension development is likely to reflect a combination of these factors. Interventions that directly interrupt renal sympathetic signaling show promising results in the treatment of resistant hypertension. CONCLUSIONS The mechanisms underlying the development of neurogenic hypertension are beginning to be elucidated, thanks to technological advancements that enable the direct measurement of RSNA. Determining factors associated with hypertension development will help to identify strategies to mitigate disease as well as provide scientific support for novel nonpharmacologic therapies.