Fifty years after its discovery, aldosterone continues to stimulate interest as a therapeutic target. Early studies focused on aldosterone’s actions on hypertension, the kidney, and electrolyte handling. More recently, its actions on the heart and cardiovascular system have become more apparent. Aldosterone causes cardiac fibrosis and remodeling, and stimulates neurohormonal systems that adversely affect the cardiovascular system. Aldosterone antagonism attenuates these negative effects. Clinical studies have applied this science and demonstrated improved morbidity and mortality with aldosterone blockade, specifically in patients with chronic heart failure and patients who are postmyocardial infarction and with depressed left ventricular function. This article will address the pathophysiology of aldosterone in cardiac fibrosis and remodeling, review the current clinical trial data, and explore the application of aldosterone blockade in an expanded heart failure population. The Randomized Aldactone Evaluation Study showed that the aldosterone antagonist spironolactone reduced mortality when compared to placebo in patients with chronic advanced heart failure. Similarly, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study demonstrated a significant reduction in mortality and hospitalizations for patients randomized to the aldosterone antagonist eplerenone. A more provocative question is whether aldosterone antagonism will afford the same protection in patient populations with heart failure and preserved left ventricular function. Clinical trials are underway, and results are eagerly awaited.