Metabolic pathways are controlled at different levels in response to environmental or hormonal stimuli. This control is achieved, at least in part, at the transcriptional level of gene expression. The regulation of gene expression is executed by specific transcription factors, but there is another level of regulation by a set of proteins that modulate these factors called transcriptional coactivators. In mammals, one of the most characterized examples of regulation of metabolic pathways by transcriptional coactivators is peroxisome proliferator-activated receptors gamma (PPARgamma) coactivator-1 alpha (PGC-1alpha). PGC-1alpha is activated by signals that control energy and nutrient homeostasis. Notably, PGC-1alpha induces and coordinates gene expression that stimulates mitochondrial biogenesis and a thermogenic program in brown fat, fiber-type switching in skeletal muscle, and metabolic pathways linked to the fasted response in the liver. PGC-1alpha activates gene expression through specific interaction with transcription factors that bind to the promoters of metabolic genes. These transcription factors can be ubiquitous such as the nuclear respiratory factors or tissue-enriched factors such as PPARgamma (brown fat), hepatocyte nuclear factor (HNF4alpha) (liver and pancreas) and muscle enhancer factor (MEF2s). The fact that PGC-1alpha controls important metabolic pathways in several tissues suggests that it can be a therapeutic target for antiobesity or diabetes drugs.