Heart failure is accompanied by important defects in metabolism. The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) is a powerful regulator of mitochondrial biology and metabolism. PGC-1α and numerous genes regulated by PGC-1α are repressed in models of cardiac stress, such as that generated by transverse aortic constriction (TAC). This finding has suggested that PGC-1α repression may contribute to the maladaptive response of the heart to chronic hemodynamic loads. We show here that TAC in mice genetically engineered to lack PGC-1α leads to accelerated cardiac dysfunction, which is accompanied by signs of significant clinical heart failure. Treating cardiac cells in tissue culture with the catecholamine epinephrine leads to repression of PGC-1α and many of its target genes, recapitulating the findings in vivo in response to TAC. Importantly, introduction of ectopic PGC-1α can reverse the repression of most of these genes by epinephrine. Together, these data indicate that endogenous PGC-1α serves a cardioprotective function and suggest that repression of PGC-1α significantly contributes to the development of heart failure. Moreover, the data suggest that elevating PGC-1α activity may have therapeutic potential in the treatment of heart failure.