This commentary discusses the findings and profound clinical implications of a prespecified analysis of renal outcomes performed by Mann et al. in the large ONTARGET study. This study assessed the effects of the angiotensin-converting-enzyme (ACE) inhibitor ramipril and the angiotensin receptor blocker (ARB) telmisartan, separately and in combination, in patients aged at least 55 years who had established vascular disease or diabetes with organ damage. Mann et al. demonstrated that, in contrast to monotherapy with either drug, the combination of an ACE inhibitor and an ARB worsens all major renal outcomes with the exception of proteinuria. This commentary recommends that combination therapy with an ACE inhibitor and an ARB to retard progression of renal disease should be avoided in patients with proteinuria lower than 1 g per day. The utility of dual RAS blockade regimens comprising an ACE inhibitor and a direct renin inhibitor, or an ACE inhibitor or ARB plus an aldosterone blocker, remains to be determined and constitutes a high priority subject for future clinical investigation.