Mineralocorticoid receptor antagonists (MRAs) are best known as potassium-sparing diuretics due to their blockade of aldosterone action in renal epithelial tissues. They are also beneficial for the treatment of heart failure, primarily due to effects in non-epithelial tissues. Currently there are only two steroidal MRAs that have been approved for use; spironolactone (and its active metabolite canrenone) and eplerenone. However, the search is on for novel generations of MRAs with increased potency and tissue selectivity. A number of novel non-steroidal compounds are in preclinical and early development, with one agent moving to phase III trials. The development of these agents and the mechanisms for their pharmacologic superiority compared to earlier generations of MRAs will be discussed in this review.