This chapter reviews the current knowledge on the role of the immune system in MS. Much of the research on the MS immunology has focused on the role of the adaptive immune system, particularly CD4 T cells, since autoreactive myelin-specific CD4 T cells are thought to be responsible for initiating disease. The chapter discusses the contribution of innate and adaptive arms of the immune system to MS. The disease-modifying therapies (DMT) that are available for the treatment of MS have immunomodulatory effects on the immune system. The current therapeutic strategies are largely ineffective in PPMS and SPMS and therefore one of the major challenges ahead will be to develop effective therapies for use in the progressive forms of MS. Progressive MS is associated with neurodegenerative processes secondary to the inflammation during RRMS. There is an increasing evidence of an important role for the innate immune system in perpetuating progressive disease.