Energy substrate preference of the heart both during and after ischemia is an important determinant of the degree of functional recovery postischemia. For instance, high rates of fatty acid oxidation after ischemia can decrease cardiac function and efficiency during reperfusion. These high rates of fatty acid oxidation can be explained by a decrease in malonyl coenzyme-A (CoA) levels, a potent inhibitor of mitochondrial fatty acid uptake. This review discusses the biochemical changes in the heart after ischemia that are responsible for these high rates of fatty acid oxidation. In particular, activation of 5′-AMP-activated protein kinase and inhibition of acetyl CoA carboxylase appear to contribute to this decrease in malonyl CoA. As a result, we propose that inhibition of 5′-AMP-activated protein kinase and/or stimulation of acetyl CoA carboxylase may be a pharmacologic approach to inhibiting myocardial fatty acid oxidation during reperfusion. Decreasing fatty acid oxidation is accompanied by a parallel increase in glucose oxidation that results in an improvement in both cardiac function and efficiency in the reperfused ischemic heart.