Hundred and fifty years after the discovery of multiple sclerosis (MS), neither the etiology nor the mechanism of disease is fully charted, and current treatment has only modest effect. The conceptual understanding of MS rests on the animal model experimental autoimmune encephalomyelitis (EAE). Based on 70 years experience with EAE, it is widely believed that MS is an inflammatory attack on myelin and neurons orchestrated by myelin specific T cells. However, evidence supporting a key role for myelin specific T cells in MS is weak, the model fails to explain how immune self-tolerance is broken, and the peculiar B cell response of MS is poorly reflected in EAE. The pathogenesis of MS should therefore be studied in tissue samples and cells from MS patients, as close to the diseased organ as possible. Studies on lymphocytes from CSF of MS patients suggest that viral infections may be involved in T cell activation, and that intrinsic collaboration between T and B cells could sustain the immune response. These observations could explain the perpetuating immune response in MS in the absence of an overt antigen.