Cardiac contractile function is strictly dependent on proper metabolic energy provision. Long-chain fatty acids and glucose are the primary energy substrates and are also indispensable for serving additional cellular roles including synthesis of biosynthetic precursors and posttranslational modification of proteins. The balance between fatty acid and glucose utilization in the heart, and myocardial contractile function appear inextricably linked. A chronic shift toward a greater dependence on a single substrate, either fatty acids or glucose, results in a metabolic imbalance and is associated with impaired cardiac function. As a result, rebalancing fatty acid and glucose utilization is an effective approach to restore cardiac contractile performance. In this article, we discuss the significance of the fatty acid-to-glucose fuel balance for maintaining homeostatic control and show recent evidence that the membrane substrate transporters cluster of differentiation 36 (CD36; for fatty acid uptake) and glucose transporter 4 (GLUT4; for glucose uptake) are key targets to recover the myocardial substrate balance. In conclusion, the fatty acid-to-glucose substrate balance is both an effective target to treat heart failure and a useful parameter to monitor myocardial function in health and disease.