MR (mineralocorticoid receptor) activation by either administration of exogenous mineralocorticoids or by allowing endogenous glucocorticoids to activate the MR has been shown to produce oxidative stress and vascular inflammation at the earliest stages of the development of cardiac fibrosis in experimental animals. These studies suggest potential mechanisms for the benefits observed in recent large scale clinical trials investigating the cardioprotective effects of MR antagonists given in conjunction with current best practice therapy for moderate-to-severe heart failure and heart failure post-myocardial infarction. Given that few patients had elevated plasma aldosterone, novel mechanisms involved in activating the MR in the failing heart are now being investigated.