The renin-angiotensin system plays a key role in the regulation of blood pressure, and blockade of this system now forms a central part of strategies to reduce the risk for cardiovascular events in high-risk patients. Both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown to be effective in lowering blood pressure and reducing the risk for cardiovascular events, but both classes of drug have some limitations. Plasma concentrations of angiotensin II increase during ACE-inhibitor therapy in some patients, partly as a result of the production of angiotensin II via non-ACE pathways; furthermore, elevated aldosterone concentrations can occur in a significant proportion of patients. ARBs block the deleterious effects of angiotensin II at angiotensin type 1 receptors irrespective of the origin of the peptide, but the beneficial effects of kinins may be diminished. ARB therapy results in activation of angiotensin type 2 receptors, resulting in potentially beneficial anti-inflammatory, antithrombotic, and antiproliferative effects, but the clinical significance of these effects remains controversial. Some ARBs, particularly telmisartan, have been shown to act as partial agonists of peroxisome proliferator-activated receptor gamma, thereby increasing insulin sensitivity. Combination therapy with ACE inhibitors and ARBs offers the potential for effective blood pressure control, decreased aldosterone production, enhanced kinin activity, and increased insulin sensitivity. The potential clinical benefits of this approach in high-risk patients are currently being investigated in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), which is comparing therapy using a combination of telmisartan plus ramipril with the use of each drug in monotherapy.