PGC-1α regulates cardiac mitochondrial biogenesis and energy metabolic gene expression, thus transcriptional regulation of PGC-1α gene expression is of great importance in understanding metabolic gene expression in cardiac health and disease. We provide evidence that estrogen related receptor α (ERRα, which also plays a role in cardiac energy metabolism, regulates expression of the PGC-1α gene via direct interaction with the PGC-1α gene promoter. In the presence of an inverse agonist to ERRα PGC-1α gene expression was significantly decreased, while over-expression of ERRα increased PGC-1α gene expression. We have also demonstrated that expression of PGC-1α was down regulated in hypoxic cardiomyocytes due to histone deacetylation. Our data identify ERRα as a novel regulator of cardiac PGC-1α gene expression, and suggests that promoter deacetylation in hypoxia plays a role in reduced PGC-1α expression. These results reveal a new mechanism that may contribute to energetic derangement in the heart during ischemia and/or failure.