The majority of patients with relapse-onset multiple sclerosis (MS) will go on to develop secondary-progressive MS (SPMS) disease, with approximately 50% developing SPMS after 10 years. It remains unknown whether the relapsing and progressive phases of MS differ qualitatively. The pathogenesis of SPMS is poorly understood. The specific role that inflammation plays in disease progression is not well defined. Immunosuppressive therapies, which are capable of reducing or stopping clinical relapses and suppressing MRI activity, generally do not stop disease progression. Recent natural history studies suggest that disease progression occurs regardless of the presence of superimposed relapses. However, poor recovery from clinical relapses does account for the acquisition of disability. Therefore, stopping relapses with appropriate therapy delays the acquisition of disability but does not necessarily delay or prevent the development of SPMS. At present, the only disease-modifying therapies licensed for use in SPMS are interferon-beta-1b in Europe and the US, and mitoxantrone in the US. These agents can only be recommended for patients who continue to have relapses. Symptomatic therapies remain the cornerstone of treatment for patients with SPMS. Delivering high-quality, effective symptomatic therapies requires a multidisciplinary approach. The aim of symptomatic therapies should not only be to reduce neurological impairments but also to decrease disability and handicap and to improve the emotional well-being and health-related quality of life of patients with SPMS.