There is strong evidence that the renal medullary circulation plays a key role in long-term blood pressure control. This, and evidence implicating sympathetic overactivity in development of hypertension, provides the need for understanding how sympathetic nerves affect medullary blood flow (MBF). The precise vascular elements that regulate MBF under physiological conditions are unknown, but likely include the outer medullary portions of descending vasa recta and afferent and efferent arterioles of juxtamedullary glomeruli, all of which receive dense sympathetic innervation. Many early studies of the impact of sympathetic drive on MBF were flawed, both because of the methods used for measuring MBF and because single and often intense neural stimuli were tested. Recent studies have established that MBF is less sensitive than cortical blood flow (CBF) to electrical renal nerve stimulation, particularly at low stimulus intensities. Indeed, MBF appears to be refractory to increases in endogenous renal sympathetic nerve activity within the physiological range in all but the most extreme cases. Multiple mechanisms appear to operate in concert to blunt the impact of sympathetic drive on MBF, including counter-regulatory roles of nitric oxide and perhaps even paradoxical angiotensin II-induced vasodilatation. Regional differences in the geometry of glomerular arterioles are also likely to predispose MBF to be less sensitive than CBF to any given vasoconstrictor stimulus. Failure of these mechanisms would promote reductions in MBF in response to physiological activation of the renal nerves, which could, in turn, lead to salt and water retention and hypertension.