Understanding the pathogenesis of complex immunologic disorders such as multiple sclerosis (MS) is challenging. Abnormalities in many different cell types are observed in the immune system and CNS of patients with MS and the identification of the primary and secondary events is difficult. Recent studies suggest that the model of MS as a disorder mediated only by T cells is overly simplistic and propose an important role for B cells in the propagation of the disease. B-cell activation in the form of oligoclonal bands (OCB) production is the most consistent immunologic finding in patients with MS. Notably, markers of B-cell activation within the CSF of patients with MS predict conversion from clinically isolated syndrome to clinically definite MS and correlate with MRI activity, onset of relapses, and disability progression. In addition, the main genetic risk factor in MS is associated with OCB production, and environmental agents associated with MS susceptibility (vitamin D and the Epstein-Barr virus) influence B-cell proliferation and function. Finally, the only cell-specific treatments that are effective in patients with MS are monoclonal antibodies targeting the B-cell antigen CD20, suggesting a potentially causative role for B cells. Based on current evidence there is no longer doubt that B cells are relevant to the etiology and pathogenesis of MS. Elucidating the role of B cells in MS will be a fruitful strategy for disease prevention and treatment.