Human essential hypertension is associated with increased activity of the sympathetic nervous system (SNS). Drugs targeting the SNS globally are effective antihypertensive agents but are also associated with numerous side effects that limit their use. The development of catheter based renal nerve ablation (CBRNA) to ablate nerves to the kidney specifically in humans shows promise as an anti-hypertensive treatment that avoids unwanted side effects. Clinical trials of CBRNA will be briefly reviewed as well as the current limitations and challenges. Beneficial unexpected “off target” effects of CBRNA have raised questions regarding the mechanism by which CBRNA decreases arterial pressure. Specifically, the contibution of ablation of renal efferent nerves that control renal function, and renal afferent nerves that modulate SNS activity, in mediating the cardiovacular responses to CBRNA is unclear. Our laboatory recently developed a novel method for targeted ablation of renal afferent nerves to address this question in preclinical models. Comparison of the cardiovascular responses to total renal denervation to afferent specific ablation suggest the underlying mechanisms are model specific. Moreover, our studies suggests an important relationship between renal nerves, renal inflammation, and hypertension. The significance of these preclinical findings to the efficacy of CBRNA in the treatment of human hypertension and other renal based cardiovacular diseases will be discussed.