In experimental autoimmune encephalomyelitis (EAE), several target antigens of encephalitogenic T- and B-cell responses have been identified. However, in human multiple sclerosis (MS) the target antigens of pathogenic T and B cells have remained conjectural. Here we discuss how recent methodological advances have offered new insights into the nature of B- and T-cell receptor repertoires expressed in MS tissues, and how novel approaches have helped to identify neurofascin as a target of anti-axonal autoantibodies in MS and EAE.