Downregulation and functional deactivation of the transcriptional coactivator PGC-1α has been implicated in heart failure pathogenesis. We hypothesized that the estrogen-related receptor α (ERRα), which recruits PGC-1α to metabolic target genes in heart, exerts protective effects in the context of stressors known to cause heart failure. ERRα-/- mice subjected to left ventricular (LV) pressure overload developed signatures of heart failure including chamber dilatation and reduced LV fractional shortening. 31P-NMR studies revealed abnormal phosphocreatine depletion in ERRα-/- hearts subjected to hemodynamic stress, indicative of a defect in ATP reserve. Mitochondrial respiration studies demonstrated reduced maximal ATP synthesis rates in ERRα-/- hearts. Cardiac ERRα target genes involved in energy substrate oxidation, ATP synthesis, and phosphate transfer were downregulated in ERRα-/- mice at baseline or with pressure overload. These results demonstrate that the nuclear receptor ERRα is required for the adaptive bioenergetic response to hemodynamic stressors known to cause heart failure.