Investigations using chronic blood pressure (BP) radiotelemetry in conscious animals have provided substantial insights into the pathophysiology of hypertensive renal damage. Normal renal autoregulation protects the renal microvasculature from significant injury in most patients with primary hypertension, unless BP exceeds a certain threshold, when malignant nephrosclerosis develops. However, if autoregulation is impaired, as in chronic renal disease and/or diabetes models, the threshold for renal damage is lowered and glomerulosclerosis (GS) increases linearly with increasing BP. Modest BP reductions are predicted to prevent malignant nephrosclerosis, but prevention of GS in patients with diabetes and chronic renal disease requires that BP be lowered well into the normotensive range, as recognized in the currently recommended BP goals. When BP load is accurately assessed in these experimental models, renal protection is proportional to the achieved BP reductions, and there is little evidence of BP-independent protection, even with agents that block the renin-angiotensin system (RAS). Recent clinical data also suggest that achieving lower BP targets might be vastly more important than the choice of therapeutic regimens. Nevertheless, because aggressive diuretic use is usually necessary to achieve such BP goals, RAS blockade should be included as initial therapy both for antihypertensive synergy and to minimize the potassium and magnesium depletion associated with diuretics.