The musculoskeletal system includes skeletal muscles, bones and innervating axons from neurons in the central and peripheral nervous systems. Together, they form the largest structure in the body. They also initiate and coordinate locomotion, provide structural stability, and contribute to metabolism and homeostasis. Because of these functions, much effort has been devoted to ascertaining the impact of acute and chronic stress, such as disease, injury and aging, on the musculoskeletal system. This review will examine the role of the nervous system in the deleterious changes that accrue in skeletal muscles and bones during the progression of neurologic diseases and with advancing age.