Direct renin inhibition is a novel strategy for the blockade of the renin–angiotensin system. In this Review, Hollenberg discusses the evidence indicating that direct renin inhibitors might block the renin–angiotensin system in the kidney more effectively than either angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers. The author also discusses the therapeutic implications of this evidence and possible mechanisms that underlie the renal effects of direct renin inhibition.