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Metabolomic analysis of the failing heart has revealed global changes in mitochondrial substrate metabolism. Peroxisome proliferator-activated receptor-\u03b1 (PPAR\u03b1) plays a critical role in synergistic regulation of cardiac metabolism through transcriptional control. Metabolic reprogramming via PPAR\u03b1 signaling in heart failure ultimately propagates into myocardial energetics. However, emerging evidence suggests that the expression level of PPAR\u03b1 per se does not always explain the energetic state in the heart. The transcriptional activities of PPAR\u03b1 are dynamic, yet highly coordinated. An additional level of complexity in the PPAR\u03b1 regulatory mechanism arises from its ability to interact with various partners, which ultimately determines the metabolic phenotype of the diseased heart. 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