Skeletal muscle fitness plays vital roles in human health and disease and is determined by developmental as well as physiological inputs. These inputs control and coordinate muscle fiber programs, including capacity for fuel burning, mitochondrial ATP production, and contraction. Recent studies have demonstrated crucial roles for nuclear receptors and their co-activators, and microRNAs (miRNAs) in the regulation of skeletal muscle energy metabolism and fiber type determination. In this review, we present recent progress in the study of nuclear receptor signaling and miRNA networks in muscle fiber type switching. We also discuss the therapeutic potential of nuclear receptors and miRNAs in disease states that are associated with loss of muscle fitness.