Multiple sclerosis (MS) is a demyelinating disease characterized by autoimmune inflammation in the central nervous system. Despite over a decade of use of interferon-β (IFN-β) in the treatment of MS, its mechanisms of action are still not fully elucidated. New data now demonstrate that the 2 important proinflammatory cytokines involved in the pathogenesis of MS, osteopontin (OPN) and interleukin-17 (IL-17), are regulated by IFN-β. This review discusses the role of OPN and IL-17 in the development of MS and how the downregulation of the levels of OPN and interleukin-17 contributes to the therapeutic effects of IFN-β in MS.