Chronic renal ischemia caused by renal artery stenosis (RAS) elicits a complex biologic response. Although the traditional pathophysiologic pathways underlying renal ischemia have been well studied, there is emerging evidence that additional mechanisms may be responsible for producing many of the hemodynamic alterations and end-organ injury seen in patients with RAS, including persistent hypertension, renal insufficiency, and cardiac disturbance syndromes. A better understanding of these mechanisms may allow earlier identification of RAS, provide markers to predict the response to revascularization, or allow unique therapeutic targets for drug development. This and a subsequent article will explore the pathophysiologic and clinical implications of chronic renal ischemia.