There have been tremendous advances in our understanding of the pathophysiology of congestive heart failure, and this has led to improvements in its treatment. Nonetheless, the prevalence of congestive heart failure and the associated mortality and morbidity continue to increase. Hence, there remains a need for additional therapeutic approaches that will complement current management with diuretics, angiotensin-converting enzyme inhibitors, other vasodilators, and digoxin. This article reviews a number of potential avenues that are currently being evaluated or remain targets for future investigation. Given our current understanding of the mechanisms of progression of left ventricular dysfunction, therapies that limit neurohormonal activation or interfere with its consequences and those that improve the balance between myocardial energy requirements and supply appear to be the most promising. Agents that improve hemodynamics without altering the underlying pathophysiology may produce short-term symptomatic improvement but have limited potential to alter the natural history of congestive heart failure. Positive inotropic therapies probably fall into this category, but most of these also appear to accelerate progression and increase mortality. In the long-term, specific interventions that reverse changes at the cellular and molecular level offer the greatest promise.