Mineralocorticoid receptor (MR) antagonism is a well-established treatment modality for patients with hypertension, heart failure, and left ventricular systolic dysfunction (LVSD) post-myocardial infarction (MI). There are emerging data showing potential benefits of MR antagonists in other cardiovascular conditions. Studies have shown association between MR activation and the development of myocardial fibrosis, coronary artery disease, metabolic syndrome, and cerebrovascular diseases. This review examines the preclinical and clinical data of MR antagonists for novel indications including heart failure with preserved ejection fraction (HFPEF), pulmonary arterial hypertension (PAH), arrhythmia, sudden cardiac death, valvular heart disease, metabolic syndrome, renal disease, and stroke. MR antagonists are not licensed for these conditions yet; however, emerging data suggest that indication for MR antagonists are likely to broaden; further studies are warranted.