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With the development of aliskiren, blockade of the renin–angiotensin–aldosterone system (RAAS) at the level of the interaction of renin with a substrate has become a clinical reality. This review covers the specific features of the first agent likely to achieve widespread clinical exposure, aliskiren. The potential of renin inhibition must be viewed in the context of the remarkable efficacy of both angiotensin-converting enzyme (ACE) inhibition and angiotensin receptor blockers (ARBs). The implications of blockade of the renin system at its rate-limiting step are reviewed, with the therapeutic implications for both the renin inhibitor employed alone or the renin inhibitor combined with an ACE inhibitor or ARB. The relevant and necessary studies are ongoing.