Skeletal muscle has a fundamentally important role in the maintenance of normal glucose homeostasis and in regulating whole-body carbohydrate metabolism. In this review, we discuss the regulation of skeletal muscle glucose transport by muscular activity and inactivity. A large number of patients routinely seen by physical therapists exhibit some form of skeletal muscle insulin resistance. Therefore, we discuss how skeletal muscle insulin resistance can be localized to a relatively small muscle mass, or in other circumstances can affect a large proportion of the muscle mass leading to disturbances in whole-body glucose homeostasis. We review the mechanisms and regulation of skeletal muscle glucose transport as background for understanding how defects in this process may contribute to the underlying pathogenesis of insulin resistance. Research into the events regulating glucose entry into skeletal muscles has considerable impact on how physical therapy exercise prescriptions may benefit patients with disturbances in carbohydrate metabolism. With an understanding of the principles of proper exercise prescription, physical therapists can use exercise training as a primary therapeutic intervention to improve local muscle and whole-body glucose utilization, and thereby minimize insulin resistance.