The clinical literature on the subject of inotropic therapy of heart failure, particularly use of digitalis glycosides, is full of contradictions. Most of this disparity can be accounted for if not reconciled by taking the methodology of the clinical trials into consideration. Because drug interventions may produce subtle effects requiring a subjective determination, the questions being asked in these studies cannot be answered without removing as many sources of bias as possible from the patient management and data analysis. If a study has not been adequately randomized, double-blinded, and placebo-controlled, the clinical findings will be inconclusive at best. Systolic myocardial dysfunction plays a pivotal role in the pathogenesis of CHF in many patients and is a prerequisite for the use of cardiotonic drugs. Although the clinical signs of heart failure may be relieved initially by diuretics and vasodilators, compensation may require the addition of a positive inotrope, particularly in advanced cases. In veterinary medicine, the choice of positive inotrope is limited to digoxin, digitoxin, dobutamine, or amrinone. Digoxin possesses superior pharmacokinetics and is the cardiac glycoside of choice for use in the dog. Dobutamine and amrinone are more potent inotropes, but since they must be administered by continuous intravenous infusion, their use is limited to critical care therapy. At the present time, only digoxin can be administered orally for sustained long-term maintenance therapy. Milrinone, a more potent derivative of amrinone, also offers this option, but it has not been available since its brief trial debut as an investigational drug. None of the nonglycoside alternatives couples the benefits of positive inotropic and negative chronotropic effects. Consequently, digoxin remains the mainstay for chronic inotropic support of the heart. Atrial fibrillation with a rapid ventricular response rate is the prime indication for digoxin. In the last few years, evidence from methodologically sound clinical trials on humans has also restored faith in the efficacy of digoxin for treating heart failure in patients with normal sinus rhythm. From these studies, the profile of a digitalis responsive heart failure patient has emerged. Digoxin is most likely to be efficacious when heart failure is associated with chronic, severe ventricular systolic dysfunction, which has resulted in ventricular dilatation. The most reliable clinical marker is the presence of a third heart sound (gallop rhythm). Although the patients in the worst heart failure generally have the shortest survival time, they may also have the most dramatic short-term clinical benefit. However, once cardiac reserve is exhausted in the terminal stages of failure, cardiotonic stimulation ceases to be effective.(ABSTRACT TRUNCATED AT 400 WORDS)