The receptor for the steroid hormone aldosterone, the mineralocorticoid receptor (MR), is a therapeutic target in cardiovascular disease. Initially used in the treatment of hypertension, pharmacological antagonists have been developed in the past and primarily used as diuretics. There is a scientific and clinical need to better understand the mechanisms of aldosterone secretion and MR activation, and to obtain molecular insights into the pathophysiological roles of MR activation, and the clinical situations where aldosterone/MR are pathogenic, which may define novel therapeutic indications of MR antagonists. Over the past 50 years, European research, both at the academic (basic and clinical research) and industrial levels, was at the cutting edge in the field allowing innovative development of MR antagonists and insights into modes of action in heart failure with a dramatic benefit for patients survival and leading to changes of the international therapeutic guidelines. Novel cellular and molecular targets of aldosterone/MR have been identified in the past decade as well as physiological and pathophysiological consequences in newly identified tissue targets. This original research has very important applications in clinical settings such as heart failure. The role of the aldosterone/MR system in myocardial and renal function, cardiac and renal ischemia reperfusion injury, inflammation, tissue fibrosis, skin and ocular diseases, to cite only a few, will have a major impact in diagnostics and therapeutics for these diseases in the future. The identity of signalling pathways and underlying molecular mechanisms still remain elusive and need to be analysed. This will lead to the identification of novel molecular targets opening up the range of therapeutic targets and diagnostic tools to identify patients who will benefit from MR antagonism. Finally, this basic and translational oriented research will help to define, design and validate novel MR antagonists with safer clinical properties.