Regular exercise promotes favorable structural and metabolic adaptations, especially in the skeletal muscle, to boost endurance and cardiovascular health. These changes are driven by a network of incompletely understood molecular pathways that trigger transcriptional remodeling of the skeletal muscle. In this article, we describe recent advances in the understanding of the key components of this circuitry [namely peroxisome proliferator activator receptor delta (PPARdelta), adenosine monophosphate (AMP)-activated protein kinase (AMPK), silent information regulator two protein 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha)] that govern aerobic transformation of the skeletal muscles. We also discuss recent discoveries that raise the possibility of synthetically mimicking exercise with pathway-specific drugs to improve aerobic capacity and, in turn, health.