Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) have beneficial effects in patients with cardiovascular disease and in those with diabetes-related and diabetes-independent chronic kidney diseases. These beneficial effects are independent of the antihypertensive properties of these drugs. However, ACE inhibitors, ARBs, and combinations of agents in these two classes are limited in the extent to which they inhibit the activity of the renin-angiotensin-aldosterone system (RAAS). Angiotensin breakthrough and aldosterone breakthrough may be important mechanisms involved in limiting the effects of ACE inhibitors and ARBs. Whether direct renin inhibitors will overcome some of the limitations of ACE-inhibitor and ARB therapy by blocking the deleterious effects of the RAAS remains to be proven. This important area is, however, in need of further investigation.