Skeletal muscle fitness and plasticity is an important determinant of human health and disease. Mitochondria are essential for maintaining skeletal muscle energy homeostasis by adaptive re-programming to meet the demands imposed by a myriad of physiologic or pathophysiological stresses. Skeletal muscle mitochondrial dysfunction has been implicated in the pathogenesis of many diseases, including muscular dystrophy, atrophy, type 2 diabetes, and aging-related sarcopenia. Notably, exercise counteracts the effects of many chronic diseases on skeletal muscle mitochondrial function. Recent studies have revealed a finely tuned regulatory network that orchestrates skeletal muscle mitochondrial biogenesis and function in response to exercise and in disease states. In addition, increasing evidence suggests that mitochondria also serve to "communicate" with the nucleus and mediate adaptive genomic re-programming. Here we review the current state of knowledge relevant to the dynamic remodeling of skeletal muscle mitochondria in response to exercise and in disease states.