Chronic kidney disease (CKD) represents a global health concern, and its prevalence is increasing. The ultimate therapeutic option for CKD is kidney transplantation. However, the use of drugs that target specific pathways to delay or halt CKD progression, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors is limited in clinical practice. Mineralocorticoid receptor activation in nonclassical tissues, such as the endothelium, smooth muscle cells, inflammatory cells, podocytes, and fibroblasts may have deleterious effects on kidney structure and function. Several preclinical studies have shown that mineralocorticoid receptor antagonists (MRAs) ameliorate or cure kidney injury and dysfunction in different models of kidney disease. In this review, we present the preclinical evidence showing a benefit of MRAs in acute kidney injury, the transition from acute kidney injury to CKD, hypertensive and diabetic nephropathy, glomerulonephritis, and kidney toxicity induced by calcineurin inhibitors. We also discuss the molecular mechanisms responsible for renoprotection related to MRAs that lead to reduced oxidative stress, inflammation, fibrosis, and hemodynamic alterations. The available clinical data support a benefit of MRA in reducing proteinuria in diabetic kidney disease and improving cardiovascular outcomes in CKD patients. Moreover, a benefit of MRAs in kidney transplantation has also been observed. The past and present clinical trials describing the effect of MRAs on kidney injury are presented, and the risk of hyperkalemia and use of other options, such as potassium binding agents or nonsteroidal MRAs, are also addressed. Altogether, the available preclinical and clinical data support a benefit of using MRAs in CKD, an approach that should be further explored in future clinical trials.Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.