There is good evidence that the renal medulla plays a pivotal role in long-term regulation of blood pressure. ‘Renal medullary’ blood pressure regulating systems have been postulated to involve both exocrine (pressure natriuresis/diuresis) and endocrine [renal medullary depressor hormone (RMDH)] functions. However, recent studies indicate that pressure diuresis/natriuresis dominates the antihypertensive renal response to increased renal perfusion pressure, suggesting little physiological role for a putative RMDH in compensatory responses to acutely increased blood pressure. The medullary circulation appears to play a key role in mediating pressure diuresis, although the precise mechanisms involved remain controversial. Counter-regulatory vasodilator mechanisms (e.g. nitric oxide), at least partly mediated through cross-talk between the vasculature and the tubular epithelium, protect the medullary circulation from the vasoconstrictor effects of hormonal factors such as angiotensin II. These mechanisms also appear to contribute to compensatory responses to increased salt intake in salt-resistant individuals. Failure of these mechanisms predisposes the organism towards the development of hypertension, appears to underlie the development of some forms of experimental hypertension, and may even contribute to the pathogenesis of essential hypertension.