Mineralocorticoid receptor antagonists (MRAs) are highly effective therapies for cardiovascular and renal disease. However, the widespread clinical use of currently available MRAs in cardiorenal medicine is hampered by an increased risk of hyperkalemia. The mineralocorticoid receptor (MR) is a nuclear receptor responsible for fluid and electrolyte homeostasis in epithelial tissues, whereas pathophysiological MR activation in nonepithelial tissues leads to undesirable pro-inflammatory and pro-fibrotic effects. Therefore, new strategies that selectively target the deleterious effects of MR but spare its physiological function are needed. In this review, we discuss recent pharmacological developments starting from novel non-steroidal MRAs that are now entering clinical use, such as finerenone or esaxerenone, to concepts arising from the current knowledge of the MR signaling pathway, aiming at receptor-coregulator interaction, epigenetics, or downstream effectors of MR.