Renal denervation reduces arterial pressure in treatment resistant hypertensive patients. Although increased efferent renal sympathetic nerve activity (ERSNA) likely contributes to the hypertension in these patients, it cannot be excluded that some of the reduction in arterial pressure produced by the renal denervation procedure is related to removal of excitatory reflexes originating in the kidney. Support for this hypothesis is derived from the findings that the fall in arterial pressure produced by renal denervation was associated with reduction in muscle sympathetic nerve activity. In contrast to the sympathetic nerves which innervate most structures in the kidney, including the vasculature, tubules, juxtaglomerular cells and the renal pelvic wall, the majority of the afferent renal nerves are located in the renal pelvic wall, where many of the afferent nerves are found close to the sympathetic nerves. In many instances, the efferent and afferent renal nerve fibers are intertwined providing anatomical support for an interaction between the efferent sympathetic and afferent renal nerves. The afferent renal nerves can be activated by increases in renal pelvic pressure within the physiological range (3-5 mmHg). In healthy normotensive rats, activation of these mechanosensitive nerve fibers leads to increases in afferent renal nerve activity (ARNA) which in turn lead to decreases in ERSNA and increases in urinary sodium excretion and urine flow rate, an inhibitory renorenal reflex response. ARNA may also be modulated by changes in ERSNA. Increases in ERSNA increase ARNA which in turn decreases ERSNA via activation of the inhibitory renorenal reflexes in the overall goal of maintaining low ERSNA to minimize sodium retention. Increases in ERSNA modulate ARNA by release of norepinephrine (NE). NE increases and decreases ARNA by activating α1 and α2 adrenoceptors, respectively, located on the peripheral afferent renal nerve endings. The interaction between ERSNA and ARNA in the control of sodium balance is especially important during various dietary sodium intakes. During high sodium dietary conditions, the inhibitory renorenal reflex control of ERSNA is enhanced. Conversely during low sodium dietary conditions, the renorenal reflex control of ERSNA is reduced. These are physiologically appropriate responses to maintain sodium balance during various dietary sodium conditions. Increased activation of angiotensin (ANG) II type 1 receptors in the renal pelvic area and α2 adrenoceptors on the afferent renal nerve endings contribute to the suppressed responsiveness of the afferent renal nerves in low sodium dietary conditions. In pathophysiological sodium-retaining states, characterized by increased ANG II, including hypertension and renal edema-forming diseases such as heart failure and renal failure, the inhibitory renorenal reflexes are impaired. Impairment of the inhibitory renorenal reflexes most likely contributes to the inappropriately increased ERSNA and sodium retention in these pathophysiological conditions. When the inhibitory renorenal reflexes are suppressed, there is evidence for a prevalence of excitatory reflexes originating in the kidney in various pathological conditions involving renal injury, including hypertension, heart failure and chronic renal failure. Support for this notion is derived from studies showing that denervation of the ischemic kidney reduces ERSNA and arterial pressure in renovascular hypertension. Further, selective afferent renal denervation has been shown to reduce arterial pressure in chronic renal failure, DOCA salt hypertension and to some degree in spontaneous hypertension. Among possible mechanisms is adenosine activating renal chemosensitive nerve fibers. Removal of both renal sympathetic and afferent renal nerves most likely contributes to the arterial pressure reduction following renal denervation in treatment resistant hypertensive patients, at least initially. Sympathetic nerves eventually reinnervate renal tissue. Therefore, it was thought that the long-term pressure reduction following renal denervation in patients was due to lack of afferent renal innervation. However, recent findings in rats and sheep show that the afferent nerves reinnervate renal tissue in a similar time-dependent fashion as the sympathetic nerves following renal denervation. These findings suggest that additional mechanisms, possibly related to the initial removal of the renal sympathetic/afferent nerves, are likely to contribute to the long-term arterial pressure reduction observed in drug-resistant hypertensive patients following renal denervation.