In RALES, low doses of the mineralocorticoid receptor (MR) antagonist spironolactone, added to standard of care for severe heart failure, improved survival by 30% and lowered hospitalization by 35%. Animal studies with the selective MR antagonist eplerenone have similarly shown MR blockade to prevent the cerebral, renal and coronary vascular inflammatory response to elevated aldosterone levels. There is now general acceptance that aldosterone concentrations inappropriate for salt status have major deleterious effects on the cardiovascular system. In many instances, however (e.g. Randomized Aldactone Evaluation Study (RALES), EPHESUS) aldosterone levels are normal and salt status unremarkable and yet MR blockade has unquestioned benefits. In these instances, there is increasing evidence that coronary and cardiac MR are activated by normal circulating cortisol levels, in the cellular context of generation of reactive oxygen species (ROS) and/or alteration in intracellular redox status. MR in VSMC and cardiomyocytes are normally predominantly occupied by cortisol in tonic inhibitory mode. Blockade of 11beta hydroxysteroid dehydrogenase type II (11betaHSD2) or ROS generation both serve to activate cortisol-MR complexes, thus mimicking the effects of mineralocorticoid/salt imbalance on blood vessels and the heart. In RALES and EPHESUS, it is likely that the antagonists are blocking normal levels of cortisol, not aldosterone, from activating MR in the context of tissue damage and ROS generation. If this is the case, MR antagonists may be of wide therapeutic potential in cardiovascular disease and not confined to those characterized by aldosterone/salt excess. Finally, the pathophysiologic roles of always-occupied MR in 'unprotected' tissues such as cardiomyocytes or neurons in response to altered intracellular redox status remain to be explored.