The disease-modifying therapies approved to treat relapsing–remitting multiple sclerosis (MS) are less effective in patients with progressive disease, with benefit largely limited to patients with recent inflammatory disease activity. Novel treatment approaches such as neuroprotective agents and repair-promoting strategies are needed to treat progressive disease, which appears to result from more compartmentalized inflammation, diffuse tissue damage, and neurodegeneration. The development of effective therapeutic strategies for progressive MS will require sensitive methods to quantify disability and detect ongoing worsening or improvement and better understanding of the pathogenesis of progression.