For 50 years aldosterone has been thought to act primarily on epithelia to regulate fluid and electrolyte homeostasis. Mineralocorticoid receptors (MR), however, are also expressed in nonepithelial tissues such as the heart and vascular smooth muscle. Recently pathophysiologic effects of nonepithelial MR activation by aldosterone have been demonstrated, in the context of inappropriate mineralocorticoid for salt status, including coronary vascular inflammation and cardiac fibrosis. Consistent with experimental studies, clinical trials (RALES, EPHESUS), have demonstrated a reduced mortality and morbidity when MR antagonists are included in the treatment of moderate-severe heart failure. The pathogenesis of MR-mediated cardiovascular disease is a complex, multifactorial process that involves loss of vascular reactivity, hypertension, inflammation of the vasculature and end organs (heart and kidney), oxidative stress and tissue fibrosis (cardiac and renal). This review will discuss the mechanisms by which MR, located in the various cell types that comprise the heart, plays a central role in the development of cardiomyocyte failure, tissue inflammation, remodelling and hypertension.