Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system. Although the immune system seems to play an important role in the pathogenesis of disease, target antigens are still uncertain and pathways leading to tissue destruction have not been fully elucidated. Recent studies have significantly contributed to a better understanding of the disease process and broadened our view on possible scenarios of disease initiation and progression. We review the role of the immune system for the manifestation and evolution of MS and discuss different pathogenetic concepts. We conclude with an outlook on future strategies to identify the cause of MS.