Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) that leads to changes of nerve conduction due to damage of CNS- resident cells, primarily oligodendrocytes and neurons. CD4+ T cells are of primary importance in the immune cascades leading to tissue damage, but also CD8+ T cells, NK cells and B cells and antibodies contribute to tissue damage. In addition, the innate immune response and mainly microglial cells participate in the events leading to lesions. There are different types of MS and possibly this is due to different underlying immune mechanisms. The current treatment options mainly affect the immune response but have not much influence on secondary signaling changes in astrocytes and neurons which contribute to constant disease progression. The immune response in MS must be seen in the systemic context and there are strong indications that the gut and lung immunity affect MS disease precipitation. The strongest genetic influence in MS is mediated by the HLA class II genes and in Western Europeans and North Americans the disease is associated with HLA-DR2b. Possibly this is due to presentation of a set of specific antigens in context of this HLA allele. Novel data indicates that the immune response in MS is not only focused on certain myelin proteins like myelin basic protein (MBP) but to additional astrocytic and neuronal proteins, which is also mirrored in the pathology. While in the past the disease has been considered as mainly a white matter disease, nowadays it is clear that also grey matter is affected by the aberrant immune response. Still much needs to be learned regarding the underlying events in MS. This expanded knowledge is important to finally discover curative therapies.