The recent clinical trials RALES and EPHESUS have shown that mineralocorticoid receptor (MR) antagonists added to standard of care substantially increase survival and decrease hospitalization in patients with heart failure. In both trials aldosterone levels and sodium status were unremarkable. Most epithelial and vascular smooth muscle cell MR are normally ‘protected' by 11β-hydroxysteroid dehydrogenase, but are nonetheless normally largely occupied but not activated by glucocorticoids. When intracellular NADH rises in response to enzyme blockade or generation of reactive oxygen species MR are activated by glucocorticoids, mimicking the cardiovascular effects of inappropriate aldosterone for salt status. This may represent a novel face of MR activation in vascular inflammation and in ‘non-protected' tissues, such as cardiomyocytes in heart failure.