Transcriptional coactivators can be important targets for physiologic regulation. PPARgamma coactivator-1alpha (PGC-1alpha), in cooperation with several transcription factors, has emerged as a key regulator of several aspects of mammalian energy metabolism including mitochondrial biogenesis, adaptive thermogenesis in brown adipose tissue, glucose uptake, fiber type-switching in skeletal muscle, gluconeogenesis in liver and insulin secretion from pancreas. Recent studies have shown a reduced expression of PGC-1alpha in skeletal muscle of diabetic and prediabetic humans. Moreover, expression of PGC-1alpha in white fat cells activates a broad program of adaptive thermogenesis characteristic of brown fat cells. PGC-1alpha could be a target for antiobesity or diabetes drugs. The aim of this article was to summarize the molecular mechanisms and biological programs controlled by the transcriptional coactivator PGC-1alpha.