One of the major goals of biomedical research is to reveal the pathomechanisms that lead to a disease on a level on which diagnostic criteria and causal therapies can be designed. The understanding and treatment of multiple sclerosis (MS) is still far from this goal, but exciting developments are on the way. MS is thought to be an autoimmune disease that is mediated by brain tissue-reactive lymphocytes, T cells and B cells, but so far these lymphocytes could not be reliably detected. This article highlights recent developments that permit the detection of autoreactive B cells in MS, the implications of this finding for early diagnosis of the disease, monitoring its activity, and eventually for gaining insight into the specific immune pathology that drives MS.