Although angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and β-blockers have been proved to reduce mortality in patients with heart failure post-acute myocardial infarction (AMI), studies show that these agents are consistently underused in this population. Further, morbidity and mortality remain high even when standard-of-care therapies are applied. Thus, new strategies have been sought to better counteract the maladaptive effects of neurohormonal stimulation in post-AMI heart failure. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that the selective aldosterone blocker eplerenone, when used in addition to standard therapy, results in significant incremental improvements in survival and morbidity and is safe and well tolerated in this setting. Based on this, major therapeutic guidelines in the United States and Europe now strongly recommend that all eligible patients with concomitant heart failure post-AMI be treated with an aldosterone blocker in addition to an ACE inhibitor (or an ARB) and a β-blocker. To achieve needed improvements in outcomes in this population, early and consistent initiation of these evidence-based, guideline-recommended therapies in all eligible patients is crucial.