Investigations of biological programs that are controlled by gene transcription have mainly studied the regulation of transcription factors. However, there are examples in which the primary focus of biological regulation is at the level of a transcriptional coactivator. We have reviewed here the molecular mechanisms and biological programs controlled by the transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha). Key cellular signals that control energy and nutrient homeostasis, such as cAMP and cytokine pathways, strongly activate PGC-1 alpha. Once PGC-1 alpha is activated, it powerfully induces and coordinates gene expression that stimulates mitochondrial oxidative metabolism in brown fat, fiber-type switching in skeletal muscle, and multiple aspects of the fasted response in liver. The regulation of these metabolic and cell fate decisions by PGC-1 alpha is achieved through specific interaction with a variety of transcription factors such as nuclear hormone receptors, nuclear respiratory factors, and muscle-specific transcription factors. PGC-1 alpha therefore constitutes one of the first and clearest examples in which biological programs are chiefly regulated by a transcriptional coactivator in response to environmental stimuli. Finally, PGC-1 alpha's control of energy homeostasis suggests that it could be a target for anti-obesity or diabetes drugs.