While immune modulation therapies have seen recent tremendous success in relapse remitting multiple sclerosis (MS), our limited knowledge of pathogenesis hampers the development of effective treatments for progressive MS (PMS). In this article, I review the results of completed clinical trials for disease–modifying drugs and their mode of action and discuss the future directions for the treatment of PMS. Those results indicate that, besides the immunoregulatory effects in the periphery, the transition into the central nervous system and the functional modification of resident immune cells such as microglia as well as lymphocytes are indispensable for the next–generation drugs.