Mineralocorticoid receptor antagonists (MRAs) have significantly evolved since the introduction of the first steroidal MRA, spironolactone, in the 1950s. Initially discovered for treating hypertension and heart failure (HF), the clinical applications of MRAs have been expanded to chronic kidney disease (CKD) and diabetic nephropathy. Steroidal MRAs, such as spironolactone and eplerenone, effectively suppress mineralocorticoid receptor activation but are associated with side effects like hyperkalemia and endocrine abnormalities. Current research aims to optimize MRAs further for broader therapeutic applications, including nondiabetic kidney and cardiovascular diseases, and to improve safety profiles. In this review, we reflect on the historical development, classification, evolution, major clinical trials, and future prospects of MRAs.