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Digoxin improves exercise tolerance and reduces hospitalizations in patients with systolic heart failure, but its use has declined progressively for the past two decades. The Digitalis Investigation Group trial showed that digoxin reduced hospitalizations but had a neutral effect on total mortality. There was evidence that mortality caused by worsening heart failure was less, but there was also a signal suggesting an increase in other cardiac (presumed arrhythmic) death. Use of digoxin has declined substantially and recent guideline recommendations have significantly de-emphasized the importance of this drug in the management of heart failure. Two developments suggest that re-evaluation of the contemporary role of digoxin in the management of heart failure with reduced ejection fraction is warranted. First, heart failure remains progressive, characterized by chronic debility, exercise intolerance, and frequent and costly hospitalizations, despite evidence-based drug and device therapies that prolong survival. Health economics have made reducing hospitalizations in patients with heart failure a major priority. Second, a strong association has emerged between serum concentration and the safety and efficacy of digoxin, which indicates a change in our approach to dosing this agent is needed. Experimental and clinical results suggest that optimizing therapeutic benefit and avoiding harm means dosing to achieve low serum digoxin concentrations (0.5–0.9 ng/mL). Digoxin is an inexpensive agent and the totality of evidence indicates that it reduces hospitalizations and improves symptoms safely when dosed to achieve low serum concentrations. These findings suggest digoxin should have a more prominent therapeutic role in patients with heart failure and reduced ejection fraction.