Angiotensin II has diverse effects on cardiovascular structure and function, and hence drugs that inhibit the formation or activity of this peptide have attained a central position in the prevention of morbidity and mortality from cardiovascular causes. The recent ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) has shown that, in patients with vascular disease or patients with diabetes who were at high risk of cardiovascular events, the angiotensin II receptor blocker telmisartan is noninferior to the angiotensin-converting enzyme inhibitor ramipril in preventing such events, despite the ONTARGET patients receiving better background preventive therapy than those enrolled in the earlier Heart Outcomes Prevention Evaluation (HOPE) study. In addition, telmisartan offers superior tolerability to that of ramipril. Moreover, the finding in this study that combination therapy with telmisartan and ramipril produced no further reduction in cardiovascular events than either drug alone, despite producing greater reductions in blood pressure, highlights the potential importance of endothelial effects of renin-angiotensin system blockade in cardiovascular protection.