The unraveling of the role of the renin–angiotensin system (RAS) in health and disease is an example of how basic and applied scientists can decipher a complex biological system to better understand the pathophysiology of disease. Moreover, clinicians have been provided with drugs to modulate the RAS, including the angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). ACE inhibitors and ARBs have revolutionized the way in which many diseases are treated, including hypertension, heart failure, diabetes mellitus, and kidney disease. Yet, despite the undoubted successes of these drugs, cardiovascular morbidity and mortality remain high. Clearly, lower blood pressure goals may be required. Because ACE inhibitors and ARBs target specific areas of the RAS, more impressive results might be obtained with a more global reduction in RAS activity. This article examines the results of clinical trials of ACE inhibitors and ARBs and assesses the potential for improving outcomes through a more global inhibition of the RAS with renin inhibitors.