Because all clinically approved angiotensin-receptor blockers (ARBs) have good safety profiles and share the ability to block angiotensin II type 1 (AT1) receptors and reduce blood pressure, it is tempting to assume that all ARBs will yield equivalent degrees of cardiovascular protection. However, such a belief depends on the tacit assumption that with appropriate dosing, all ARBs will also share the same ability to counteract other pathogenetic determinants of cardiovascular disease beyond those involving the renin-angiotensin system. Accumulating evidence from multiple laboratories has shown that this assumption is incorrect and indicates that some ARBs are characterized by an unusual ability to affect potential mechanisms of cardiovascular disease involving more than just the renin-angiotensin system. Ultimately, large-scale clinical trials will be required to better understand the clinical importance of the mechanistic effects of ARBs that involve more than just inhibition of the renin-angiotensin system. Meanwhile, given the many functional differences among ARBs that are not mediated by AT1 receptor blockade, the effects of any particular ARB on cardiovascular outcomes should not be assumed to apply equally to all ARBs let alone to other drugs that inhibit the renin-angiotensin system through different mechanisms.