© 2017 Elsevier Inc. Despite its being characterized in the late 1800s, multiple sclerosis (MS) continues to debilitate and burden patients and caregivers alike. With its root causes still unknown, this progressive neuropathology manifests in myriad symptoms and sclerotic central nervous system (CNS) lesions. This chapter outlines some of the hypothesized genetic and environmental causes, primary symptomatic elements, and clinical management techniques of MS. In particular, this chapter summarizes the history, components, and preliminary results of a form of physical rehabilitation, termed constraint-induced movement therapy (CI therapy), which has preliminary evidence for success with improving real-world physical function as well as structural neuroplasticity of the CNS. We review prior neuroimaging findings of CI therapy and describe potential mechanisms behind the treatment success. We suggest that this efficacious motor therapy may have an important role for treating patients with progressive MS.