In skeletal muscle, environmental demands activate signal transduction pathways that ultimately promote adaptive changes in myofiber cytoarchitecture and protein composition. Recent advances in determining the factors involved in these signal transduction pathways provide insight into possible therapeutic methods to remodel skeletal muscle.Advances in genetic engineering have allowed the introduction or depletion of factors within the myofiber, facilitating the evaluation of signaling factors during muscle remodeling. Using transgenic mouse models, activation of specific signaling pathways promoted type I oxidative myofibers, increased the fatigue resistance of muscle, increased skeletal muscle mass and ameliorated muscle injury in myopathic mouse models. Moreover, new technologies are being used to generate global gene and protein expression profiles to identify new factors involved in skeletal muscle remodeling. Finally, small RNAs, microRNAs, are emerging as powerful regulators of gene expression in most tissues, including skeletal muscle. Recent findings predict that targeted delivery of miRNAs will specifically manipulate genes and if used therapeutically will revolutionize clinical medicine.Developing drugs to target signaling pathways associated with remodeling myofibers provides a possible therapeutic approach to combat skeletal muscle disease. In addition, genome-wide technologies can identify new biomarkers capable of diagnosing myopathies and determine a patient's response to therapy. Furthermore, therapeutic strategies are being designed to target microRNAs in anticipation of blocking gene repression correlated with muscle pathology.