Although supported by 2 centuries of anecdotal clinical evidence, the safety and efficacy of the cardiac glycosides for the treatment of congestive heart failure due to systolic ventricular dysfunction had never been rigorously examined by prospective clinical trials until the past decade. A reevaluation of the appropriate role of these drugs in modern cardiovascular pharmacology was prompted by the introduction in the 1970s of new classes of drugs for the treatment of congestive heart failure and supraventricular arrhythmias. Concurrently, several reports appeared, questioning the routine prescription of digoxin for the treatment of heart failure, particularly in patients in sinus rhythm. The majority of clinical trials published since 1980, most of which examined patients with New York Heart Association class II and III congestive heart failure, indicate that digoxin with or without concomitant administration of a vasodilator lessens symptoms and reduces the morbidity associated with congestive heart failure, particularly in patients with more advanced symptoms and ventricular dysfunction. The data on efficacy are less clear in support of the routine prescription of digoxin in the treatment of mild (class I and II) congestive heart failure. Although most recent trials attest to the relative safety and efficacy of digoxin in patients with congestive heart failure whose serum levels are maintained between 1 and 2 ng/ml, there is no conclusive evidence as yet that cardiac glycosides improve survival, as has been documented for vasodilators and, in particular, angiotensin-converting enzyme inhibitors. The National Institutes of Health-sponsored Digitalis Investigators Group (DIG) trial now underway should provide an answer to this question within the next few years.