Fatty acid oxidation (FAO) is a primary energy source for meeting the heart's energy requirements^,,. Peroxisome proliferator-activated receptor-δ (PPAR-δ) may have important roles in FAO^,,,,. But it remains unclear whether PPAR-δ is required for maintaining basal myocardial FAO. We show that cre-loxP-mediated cardiomyocyte-restricted deletion of PPAR-δ in mice downregulates constitutive expression of key FAO genes and decreases basal myocardial FAO. These mice have cardiac dysfunction, progressive myocardial lipid accumulation, cardiac hypertrophy and congestive heart failure with reduced survival. Thus, chronic myocardial PPAR-δ deficiency leads to lipotoxic cardiomyopathy. Together, our data show that PPAR-δ is a crucial determinant of constitutive myocardial FAO and is necessary to maintain energy balance and normal cardiac function. We suggest that PPAR-δ is a potential therapeutic target in treating lipotoxic cardiomyopathy and other heart diseases.