Over the last two decades, the known functions of the mineralocorticoid receptor (MR) have expanded beyond regulation of sodium and potassium in epithelial cells to encompass physiological and pathophysiological effects in many different tissues. Moreover, the MR in non-epithelial tissues is characterized by the fact that the predominant ligand is cortisol in the physiological setting and thus represents an alternative signaling mechanism for this class of hormones. It is now well accepted that activation of the MR in the cardiovascular system promotes tissue inflammation and fibrosis and has negative consequences for cardiac function and patient outcome following cardiac events. Indeed blockade of the MR using of the two available antagonists (spironolactone and eplerenone) has significant cardio-protective effects in the clinical and experimental setting. Although the pathways downstream of the MR that translate receptor activation into tissue inflammation, fibrosis and dysfunction are still being elucidated, a series of recent studies using selective MR null, or MR overexpression, have offered many new insights into the role of the MR in cardiovascular disease and the control of blood pressure. Our more recent studies have also indicated that increased MR signalling in adipose tissue may contribute to metabolic dysfunction and that MR blockade determines a more favorable metabolic profile with improved glucose tolerance. Given the potential risk of side effects of current therapies, a key goal is the identification of tissue selective MR antagonists that will provide therapeutic benefits but spare renal function. As such, the specific cellular mechanisms regulated by MR located in non-epithelial cells may provide the basis for the development of targeted therapies.