Angiotensin receptor blockers (ARB) have been recommended as a first option for the management of hypertension by guidelines, particularly in patients at high cardiovascular risk. The preference for ARB in these conditions is based on their neutral metabolic effects, and on direct cardiac and renal protective effects independent of the blood pressure-lowering effect (pleiotropic effects). Nonetheless, six large clinical trials designed to demonstrate such effects in patients at high cardiovascular risk, comparing ARB with placebo, failed to demonstrate any cardiovascular protection by ARB. In two trials there was higher cardiovascular mortality in patients treated with ARB. Their putative beneficial effect in the prevention of atrial fibrillation was not confirmed in four major clinical trials specifically designed to investigate this effect. Moreover, in various recent trials, treatment with ARB led to worse renal outcomes, such as an increased incidence of microalbuminuria, renal impairment and decreased glomerular filtration rate. The role of ARB for the prevention of cardiovascular and renal disease should be re-examined.