Effective treatment of high blood pressure levels represents a key strategy for reducing global cardiovascular risk. Other factors, beyond blood pressure control, however, appear to be of potential relevance in reducing the risk related to hypertension. Recent clinical trials have demonstrated that those pharmacological agents that counteract the renin-angiotensin system may confer additional clinical benefits across the spectrum of cardiovascular disease, beyond their blood pressure-lowering properties. These studies are largely based on the use of an antihypertensive strategy, based on the association between angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ARBs) and low-dose thiazide diuretics or calcium channel blockers. Over the last few decades, clinical trials have also tested the potential effects of combination therapy based on the association between angiotensin-converting enzyme inhibitors or ARBs and other renin-angiotensin system-blocking agents, including mineralocorticoid receptor antagonists and, more recently, renin inhibitors. This review highlights the evidence derived from recent clinical trials, supporting a role for pharmacological strategies based on ARBs in primary and secondary prevention of cardiovascular and renal disease.