It is now apparent that the myocardium in patients with congestive heart failure (CHF) is not normal, because important structural and molecular changes modify function in these hearts. It appears likely that the myocardium in these patients with CHF becomes unable to provide enough chemical energy to meet its mechanical requirements. If this interpretation is correct, the resulting condition of “energy starvation” would have several important implications for therapy. For example, inotropic stimulation, by increasing energy expenditure, could contribute to the progressive myocardial cell death that characterizes end-stage cardiac hypertrophy. Conversely, the reduction in myocardial contractility that develops in the chronically overloaded heart reduces myocardial energy expenditure, and changes in the expression of myosin isoforms improve cardiac efficiency. Therefore, an important goal of therapy in the patient with CHF is to reduce energy expenditure by unloading the failing heart and, in some cases, by administration of negative inotropic drugs.