Digitalis plays an important role in the treatment of patients in whom systolic dysfunction is a major component. Although its therapeutic benefits were demonstrated more than two centuries ago, the efficacy of digitalis in the treatment of patients in normal sinus rhythm with heart failure has remained controversial. Further, beneficial effects beyond a direct inotropic or hemodynamic benefit may account for much of the clinical outcome in humans. The absence of a significant reduction in mortality in a large prospective trial (Digitalis Investigation Group [DIG] trial) is balanced against the clinical benefit demonstrated in two independent digoxin withdrawal studies.