Despite its positive inotropic effects and its propensity to stimulate the renin system, adrenomedullin (AM) is hypotensive as a result of dramatic reductions in peripheral resistance. Furthermore, it does not appear to increase aldosterone secretion in spite of often vigorous activation of circulating renin. Hence, we postulate that AM may act as a functional antagonist to angiotensin II both in the vasculature and the adrenal glomerulosa. In the series of studies performed in sheep and human (normal and circulatory disorders) reviewed here, we report significant hemodynamic and hormonal actions of AM. These actions include consistent reduction of arterial pressure associated with rises in cardiac output and hence a dramatic reduction in calculated total peripheral resistance (CTPR). AM also consistently attenuates the pressor effects of angiotensin II (but not norepinephrine). Furthermore, AM consistently increases plasma renin activity (PRA) and induces either a reduction in plasma aldosterone, dissociation between aldosterone/PRA ratio, or attenuation of angiotensin II-induced aldosterone secretion. Thus, these results clearly point to a role for AM in pressure and volume homeostasis acting, at least in part, by interaction with the renin-angiotensin-aldosterone system (RAAS).