During the past 10 years, more than 80 orally active vasodilator and inotropic agents have been tested in the clinical setting to evaluate their potential utility in the treatment of chronic heart failure. Although the initial reports of all of these drugs suggested that each represented a major therapeutic advance, only three agents--digoxin, captopril and enalapril--have produced consistent long-term hemodynamic and clinical benefits in these severely ill patients. Most of the other drugs that have been tested have not (to date) distinguished themselves from placebo therapy in large-scale, controlled trials, even though these agents produce hemodynamic effects that closely resemble those seen with digitalis and the converting-enzyme inhibitors. These observations suggest that the hemodynamic derangements that characteristically accompany the development of left ventricular dysfunction cannot be considered to be the most important pathophysiologic abnormality in chronic heart failure. Although cardiac contractility is usually depressed in this disease, positive inotropic agents do not consistently improve the clinical status of these patients. Similarly, although the systemic vessels are usually markedly constricted, drugs that ameliorate this vasoconstriction do not consistently relieve symptoms, enhance exercise capacity or prolong life. Hence, correction of the central hemodynamic abnormalities seen in heart failure may not necessarily provide a rational basis for drug development, and future advances in therapy are likely to evolve only by attempting to understand and modify the basic physiologic derangements in this disorder.