Thyroid hormone (T3) has a profound influence on normal development, differentiation and metabolism. T3 induces complex gene expression patterns raises the question of how these expression patterns might be regulated. Since the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) induces very similar cellular energy metabolic pathways, we investigated the molecular mechanism of T3 regulation of PGC-1alpha. PGC-1alpha is rapidly regulated by T3, both in vivo and in cell culture. Transient transfection experiments demonstrated binding of the thyroid hormone receptor (TR) to a response element located at -4kb upstream of the transcriptional start site within the PGC-1alpha gene. Introducing of a single copy of the -4kb TRE in a heterologous promoter context is sufficient to maintain T3 responsiveness. Chromatin immunoprecipitation analysis revealed increased histone acetylation upon stimulation of T3. Finally, TR binds the -4kb TRE in electrophoretic mobility shift assays, identifying PGC-1alpha as a direct target of TR action. Since T3 directly regulates PGC-1alpha and PGC-1alpha coactivates liganded TR, we suggest an autoregulatory feed-forward loop of PGC-1alpha activation upon T3 treatment.