Hypertension is a significant risk factor for cardiovascular disease (CVD), including stroke, myocardial infarction, kidney disease and heart failure. Considerable research has been undertaken to delineate the differential effects of various classes of antihypertensive agents in delaying or preventing cardiovascular morbidity and mortality. Although possible benefits may result from specific agents or classes of agents in certain high-risk subgroups, prompt and intensive blood pressure (BP) reduction to target levels remains the most crucial factor in this benefit. Despite this, the BP remains above the target level in a large majority of patients, reinforcing the need for improved treatment paradigms. Among antihypertensive agents, inhibitors of the renin-angiotensin system--angiotensin-II receptor blockers and angiotensin-converting enzyme inhibitors--and long-acting dihydropyridine calcium channel blockers (DHP-CCBs) have been shown to provide safe, effective and well-tolerated BP control. These agents have also been proven as effective as, and in some cases superior to, other classes of agents in reducing cardiovascular morbidity and mortality. As the majority of high-risk patients require at least two and possibly even three medications to achieve the target BP, combination therapy with these two classes of drugs is a rational approach to therapy. Whether fixed-dose combination therapy with a renin-angiotensin system inhibitor plus a DHP-CCB affords greater clinical benefit compared with other combination regimens remains to be determined in large, prospective clinical trials. Meanwhile, such a combination offers effective, convenient, well-tolerated control of the most important modifiable risk factor for CVD.