Cardiovascular disease is a leading cause of mortality among patients with diabetes, and heart failure exists even in the absence of coronary disease. Myocardial metabolism is altered in the diabetic heart as a result of changes in substrate availability secondary to insulin resistance. The nuclear receptor peroxisome proliferator activated receptor-alpha (PPARα) and PPAR-gamma coactivator-1alpha (PGC-1α) play important roles in transcriptional regulation of myocardial metabolism and contribute significantly to the changes that occur in the diabetic heart. This review summarizes the role of PPARα and PGC-1α in myocardial metabolism in the normal heart and in the diabetic heart.