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The renin-angiorensin system (RAS) is an important regulator of vascular volume and cardiovascular structure. Inhibitors of the RAS appear to provide benefits in addition to those associated with blood pressure lowering in disorders such as diabetic nephropathy, and congestive heart failure. Early successes led to the speculation that improved blockade of the RAS could produce further benefits. Although improved blockade can be achieved by combining angiotensin converting enzyme inhibitors and angiotensin receptor blockers, there is no convincing evidence that this strategy can substantially improve the outcome of hypertension, congestive heart failure, or diabetes over that currently achievable. There is even evidence to suggest that too complete a blockade of the RAS could be detrimental, likely as the result of diminished cardiovascular homeostasis. Collectively, these observations suggested that the benefits of strategies directed at the RAS may have achieved their maximal potential to produce benefit. However, it has become increasingly clear that the renin-angiotensin system is substantially more complex than previously appreciated. Effector proteins other than angiotensin II have been identified and tissue/cellular RASs have been defined. As a result, rather than closing the book on RAS- based therapeutics, current research may actually be opening an entirely new chapter.