Skeletal muscle is comprised of heterogeneous muscle fibers that differ in their physiological and metabolic parameters. It is this diversity that enables different muscle groups to provide a variety of functional properties. In response to environmental demands, skeletal muscle remodels by activating signaling pathways to reprogram gene expression to sustain muscle performance. Studies have been performed using exercise, electrical stimulation, transgenic animal models, disease states, and microgravity to show genetic alterations and transitions of muscle fibers in response to functional demands. Various components of calcium-dependent signaling pathways and multiple transcription factors, coactivators and corepressors have been shown to be involved in skeletal muscle remodeling. Understanding the mechanisms involved in modulating skeletal muscle phenotypes can potentiate the development of new therapeutic measures to ameliorate muscular diseases.