Multiple sclerosis is a chronic inflammatory disease of the white and grey matter which results in irrevocable axonal and neuronal damage. Grey matter injury is widespread and reflects disability to a greater extent than do white matter lesions. Growing understanding of the immunopathology of multiple sclerosis is leading the way to the identification and testing of untapped targets that may offer new and more specific ways to treat the disease. For example, data from animal models support a two-step pathological process in multiple sclerosis, whereby T cells initially induce inflammation and open up the blood-brain barrier, which then allows access to antibodies which aggravate tissue damage. Determination of the specificity of the invading T cells and the autoantibodies that cause disease is a major focus of current research. The discovery of anti-aquaporin-4 autoantibodies in patients with neuromyelitis optica and of anti-MOG antibodies in a subset of children with paediatric autoimmune demyelinating disease are promising steps in this direction. Recently, the axoglial antigens neurofascin and contactin-2/TAG-1, which are localised around the node of Ranvier, were identified as targets of an autoimmune response in multiple sclerosis. Such an autoimmune response might induce axonal injury and direct the immunopathological response to the grey matter. It is to be hoped that the outcome of such investigations will lead to the identification of patient subgroups based on their autoreactivity and new ways to treat them safely and effectively.