Multiple sclerosis (MS) is an inflammatory demyelinating disease that targets myelin in the central nervous system (CNS), with relative sparing of axons. MS affects more than 2.5 million people worldwide and more commonly affects females. MS is prevalent in people of Caucasian descent living in the temperate regions of Europe, North America, and Australia, while it is relatively rare in Asians and Africans, indicating clear racial and geographical differences. Most MS patients initially have a relapsing-remitting phase with a mean age of onset around 30 years of age. This is termed relapsing-remitting MS (RRMS). In its natural course, after 10–20 years, about half of RRMS patients develop a secondary progressive phase with or without superimposed relapses, which is termed secondary progressive MS (SPMS). Approximately 10–20% of MS patients exhibit a relentlessly progressive course from the onset, termed primary progressive MS (PPMS). MS is assumed to be an autoimmune disease but this is not yet proven. In addition to major effects of human leukocyte antigen (HLA) class II genes (such as HLA-DRB1⃰15:01), genome-wide association studies have revealed many susceptibility genes for MS with modest effect size. The functions of these genes are mostly immune-related, supporting the autoimmune hypothesis. T helper (Th)1/Th17 cell involvement in acute relapse and acute MS lesion formation is supported by perivascular lymphocyte cuffing consisting mainly of CD4+ T cells, increased numbers of T cells showing inter- and intra-molecular epitope spreading against myelin proteins, increased cerebrospinal fluid (CSF) levels of interferon (IFN)γ, interleukin (IL)17 and downstream proinflammatory cytokines, exacerbation of disease following IFNγ administration, and increased percentages of Th1 cells secreting IFNγ and of Th17 cells secreting IL-17 at relapse. Clonal expansion of CD8+ T cells and abundant infiltration of CD8+ T cells suggest a contribution of cytotoxic T cells, presumably by acute axonal transection. Although B cell infiltration in the CNS parenchyma is not prominent, ectopic lymphoid follicles that appear to have a close correlation with subpial demyelination are often detected in the meninges. Their existence indicates an involvement of B cells in MS. The efficacy of anti-CD20 monoclonal antibody therapy also supports a B cell contribution to MS, probably through B−T cell interaction and proinflammatory cytokine production. However, no specific autoantibodies for MS have been discovered. Although our understanding of MS pathogenesis has increased remarkably in recent years, its etiology remains to be established. Recently developed disease-modifying drugs (DMDs) can efficiently suppress MS relapse but disability still progresses even with these drugs. Only one DMD is modestly effective for PPMS. The mechanism of the progressive phase remains unknown, and its elucidation and control by novel drugs are major challenges for the future.