This paper reviews the current understanding of the molecular basis of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)–mediated pathway and discusses the role of PGC-1α in skeletal muscle atrophy caused by immobilization. PGC-1α is the master transcription regulator that stimulates mitochondrial biogenesis, by upregulating nuclear respiratory factors (NRF-1, 2) and mitochondrial transcription factor A (Tfam), which leads to increased mitochondrial DNA replication and gene transcription. PGC-1α also regulates cellular oxidant–antioxidant homeostasis by stimulating the gene expression of superoxide dismutase-2 (SOD2), catalase, glutathione peroxidase 1 (GPx1), and uncoupling protein (UCP). Recent reports from muscle-specific PGC-1α overexpression underline the importance of PGC-1α in atrophied skeletal muscle, demonstrate enhancement of the PGC-1α mitochondrial biogenic pathway, and reduced oxidative damage. Thus, PGC-1α appears to play a protective role against atrophy-linked skeletal muscle deterioration.