This review covers the last 80 years of remarkable progress in the development 
of mineralocorticoid receptor (MR) antagonists (MRAs) from synthesis of the 
first mineralocorticoid to trials of nonsteroidal MRAs. The MR is a nuclear 
receptor expressed in many tissues/cell types including the kidney, heart, 
immune cells, and fibroblasts. The MR directly affects target gene 
expression-primarily fluid, electrolyte and haemodynamic homeostasis, and also, 
but less appreciated, tissue remodelling. Pathophysiological overactivation of 
the MR leads to inflammation and fibrosis in cardiorenal disease. We discuss the 
mechanisms of action of nonsteroidal MRAs and how they differ from steroidal 
MRAs. Nonsteroidal MRAs have demonstrated important differences in their 
distribution, binding mode to the MR and subsequent gene expression. For 
example, the novel nonsteroidal MRA finerenone has a balanced distribution 
between the heart and kidney compared with spironolactone, which is 
preferentially concentrated in the kidneys. Compared with eplerenone, 
equinatriuretic doses of finerenone show more potent anti-inflammatory and 
anti-fibrotic effects on the kidney in rodent models. Overall, nonsteroidal MRAs 
appear to demonstrate a better benefit-risk ratio than steroidal MRAs, where 
risk is measured as the propensity for hyperkalaemia. Among patients with Type 2 
diabetes, several Phase II studies of finerenone show promising results, 
supporting benefits on the heart and kidneys. Furthermore, finerenone 
significantly reduced the combined primary endpoint (chronic kidney disease 
progression, kidney failure, or kidney death) vs. placebo when added to the 
standard of care in a large Phase III trial.