Angiotensin II (Ang II) receptor blockers (ARBs) are highly selective for the Ang II type 1 receptor (AT1), which is a member of the G protein-coupled receptor superfamily (GPCRs), and block the diverse effects of the agonist Ang II. Many studies have shown that these agents are safe and effective. In addition to their beneficial effects against hypertension, ARBs have also been associated with the regression of left ventricular hypertrophy and a decrease in cardiovascular morbidity and mortality in patients with heart failure or hypertensive diabetic nephropathy with proteinuria. Many ARBs are available for clinical use. Since ARBs do not all have the same effects, the benefits conferred by ARBs may not be class effects. Over the past decade it has become possible to detect agonist-independent signal transduction by GPCRs, and ligands described as inverse agonists, which can block activities, have been described. One type of ARB has been shown to have inverse agonistic action in an in vitro mutagenesis study. In addition, mechanical stretch-induced signals through AT 1 receptor have been shown to be independent of Ang II stimulation, and these signals are blocked by an ARB. These findings represent an exciting new area in ARB treatment. ARB-based therapy holds the promise of reducing the incidence of cardiovascular disease. This review will address the roles of inverse agonistic action and its blockade in the cardiovascular system.