The pathogenesis of multiple sclerosis (MS), the major neurological disease of young adults in the Western world, is still poorly understood, and no effective therapy to block MS is available as yet. The clinical symptoms of MS result from inflammatory damage to the insulating myelin sheath of axons in the CNS and-at later stages-to axons themselves. A local autoimmune process involving activation of helper T cells against CNS protein components is likely to be crucial in this development. Especially at the first stages of MS, therapies aimed at the selective downregulation of MS-specific autoimmune responses may contribute to controlling the disease. Key to the success of such approaches is the identification of CNS proteins that are the target of local T cell responses. We recently identified the small heat-shock protein alpha B-crystallin as the single immunodominant myelin antigen in MS-affected myelin. This review discusses the functional and therapeutic implications of this finding along with other data on MS, and hypothesizes that an inappropriate stress response within the CNS itself is crucial as an initiating event in disease development.