Endurance exercise promotes skeletal muscle adaptation, and exercise-induced peroxisome proliferator-activated receptor gamma coactivator-1alpha (Pgc-1alpha) gene expression may play a pivotal role in the adaptive processes. Recent applications of mouse genetic models and in vivo imaging in exercise studies have started to delineate the signaling-transcription pathways that are involved in the regulation of the Pgc-1alpha gene. These studies revealed the importance of p38 mitogen-activated protein kinase/activating transcription factor 2 and protein kinase D/histone deacetylase 5 signaling transcription axes in exercise-induced Pgc-1alpha transcription and metabolic adaptation in skeletal muscle. The signaling-transcription network that is responsible for exercise-induced skeletal muscle adaption remains to be fully elucidated.