Investigations of the mechanisms that modulate energy generation during states of altered cardiac metabolism have reached a point where there is both need and demand for novel approaches. The evidence discussed here strongly suggests that both energy generation and utilization in these states may be effectively strengthened by nutritional manipulation. Compared with standard treatments for ischemia/reperfusion injury or heart failure, nutritional therapy may present an important and less toxic approach by affecting the mechanisms of energy utilization during compromised cardiac states. We provide not only a conceptual framework for further experimental studies of myocardial metabolism during ischemia and reperfusion injury but also a basis for developing clinically applicable nutrients designed to improve deranged cardiac function. The use of traditional energy substrates, in conjunction with those that may be conditionally important during compromised cardiac states, potentially offers a useful therapeutic modality in the treatment of the cardiac patient.