Modulation of the renin-angiotensin system is considered to be the most complete way to manage high-risk patients including those with hypertension. Angiotensin-converting enzyme (ACE) inhibitors are effective at reducing the morbidity and mortality of patients with overt clinical heart failure, asymptomatic left ventricular dysfunction, and uncomplicated myocardial infarction. Furthermore, recent trials like the Heart Outcomes Prevention Evaluations (HOPE) study and the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) support extending the use of ACE inhibitors to the routine/first-line treatment of patients with an increased global cardiovascular risk. Although some investigators have seen the development of angiotensin II receptor blockers (ARBs) as a more effective and tolerable way of reproducing the benefits of ACE inhibition, there remain important concerns regarding the distinct pharmacologic profiles and modes of action of these two classes of drugs. Careful evaluation of data from recent large-scale studies revealed that, unlike ACE inhibitors, ARBs are either neutral or may actually increase rates of myocardial infarction despite similar levels of blood pressure reduction. The fact that this effect is most apparent when ARBs are compared with placebo in the absence of concomitant ACE inhibitors suggests that differential effects on the angiotensin II type 2 (AT(2)) receptors may be important. Other important pharmacologic differences are also known to be present and may be of direct relevance. The weight of available evidence therefore supports the use of appropriate ACE inhibitor regimens, although not ARBs, in the treatment of global cardiovascular risk.