Exercise triggers a pleiotropic response in skeletal muscle, which results in a profound remodeling of this tissue. Physical activity-dependent muscle fiber plasticity is regulated by a number of distinct signaling pathways. Even though most of these pathways are activated by different stimuli and in a temporally and spatially separated manner during exercise, many of the major signal transduction events converge on the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) by post-translationally modifying the PGC-1α protein, modulating PGC-1α gene expression or both. In turn, depending on the cellular context, PGC-1α regulates specific gene programs. Ultimately, PGC-1α modulates most of the transcriptional adaptations of skeletal muscle to exercise. In this review, the regulation and function of this pivotal transcriptional coactivator in muscle are discussed.