Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure (HF), reduced ejection fraction (REF) with severe symptoms (RALES, spironolactone) or with mild symptoms (EMPHASIS-HF, eplerenone), and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction (MI) (EPHESUS, eplerenone). These clinical benefits are observed in addition to those of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β-blockers. The morbidity and mortality benefits of MRAs may be mediated by several mechanisms of actions, including antifibrotic mechanisms that slow HF progression, prevent or reverse cardiac remodelling, or reduce arrhythmogenesis. Both eplerenone and spironolactone have demonstrated survival benefits in individual clinical trials. Pharmacologic differences exist between the two drugs, which may be relevant for therapeutic decision-making in individual patients. Although hyperkalaemia events were reported in the major MRA clinical trials, these risks can be mitigated through appropriate patient selection, dose selection, patient education, monitoring, and follow-up. When used appropriately, MRAs significantly improve outcomes across the spectrum of patients with HFREF. Consequently, in the latest international guidelines, an MRA is strongly recommended (grade I, level of evidence A) for all patients with persisting symptoms (New York Heart Association classes IIIV) and an ejection fraction ≤35% despite treatment with an ACE inhibitor (or ARB) to reduce the risk of HF hospitalisation and the risk of premature death. As the totality of evidence grows, new strategies are needed to ensure the uptake of clinical trial evidence into clinical practice, from appropriate patient selection to optimal monitoring practices. The expansion of guideline recommendations for MRAs to include less sick patients may serve as a stimulus to develop such strategies or processes of care. MRAs are being evaluated in several new patient populations, including HF with preserved systolic function, ST segment elevation MI without HF, chronic kidney disease, end-stage renal disease on haemodialysis, resistant hypertension, atrial fibrillation, diabetic nephropathy, and other conditions in which aldosterone contributes to disease pathophysiology.