Using a functional genomic approach, we have recently shown that the orphan nuclear receptors ERRα and γ coordinate a broad transcriptional program controlling energy production and utilization in the heart. In addition, both ERRs appear to be critical for normal heart function as several of their target genes are known to be associated with human cardiomyopathies. The ability to regulate the activity of ERRα and/or ERRγ using synthetic ligands suggests the potential for new therapeutic approaches to prevent and manage cardiovascular diseases.