In many forms of heart failure a depression of myocardial performance has been identified. Ultimately this implies that a biochemical limitation of cardiac function may be the cause of the heart failure state. This limitation could involve the areas of energy metabolism, protein synthesis, or excitation-contraction coupling. Mitochondrial function and the uptake of substrates and oxygen by the failing heart cannot be implicated as causal factors in heart failure. Similarly, myocardial energy stores are adequate for normal function, and the efficiency of energy utilization is not decreased in the failing myocardium. The production of acute cardiac overload in the experimental animal causes an augmentation of protein synthesis involving increased rates of RNA production and amino acid incorporation into protein. However, the greatest portion of this activity take place in noncontractile cells. While a diminution of these processes is associated with the heart failure state, it is certainly not clear what stimulus evokes the diminution of these processes or whether they are causally related to the onset of heart failure. Finally, there is evidence that alterations of contractile state in the myocardium may be mediated by alterations in the process of excitation-contraction coupling which involves the release and reuptake of calcium ion from the sarcoplasmic reticulum. While many factors operating together may ultimately explain the onset of heart failure, a desect in excitation-contraction coupling remains the most likely single possibility.