This paper reports the rationale for the cardiovascular protective effects of ACE inhibitors (ACEI) and reviews the overall results of recent randomized clinical trials. ACEI improve the vasoconstrictive/vasodilatory balance by blocking the formation of angiotensin II and preventing the degradation of bradykinin. In vitro, animal and human experimental studies have shown that ACEI have several properties: They promote vasodilation, limit neurohormonal activation and vasoconstriction during ischemia, improve endothelial function by reducing oxidative stress, slow down the development of atherosclerosis; improve fibrinolytic balance, inhibit platelet activation and reverse negative vascular remodelling. Previous trials have shown that ACEI reduced cardiovascular events in patients with heart failure or ventricular dysfunction. These findings have recently been extended to trials using lipophilic ACEI with high affinity for tissue ACE i.e. those most likely to have high antiatherosclerotic efficacy. In PROGRESS (n = 6105), a perindopril-based regimen reduced recurrent stroke by 28% and substantially reduced cardiac outcomes among individuals with cerebrovascular disease. In HOPE (n = 9297), ramipril reduced the composite outcome (cardiovascular death, myocardial infarction and cerebrovascular accident) by 22% in patients with high cardiovascular risk. EUROPA (n = 12 218) showed that perindopril reduced cardiovascular mortality, myocardial infarction and cardiac arrest by 20% in coronary artery disease patients whatever their level of risk. The central role of long-acting lipophilic ACEI for cardiovascular protection has been clearly established and they should now be considered as a routine treatment for secondary prevention as aspirin, beta blockers and statins.