The use of antibodies against the human B cell surface protein CD20 represents the most advanced therapeutic approach among the B cell–depleting armamentarium for the treatment of autoimmune disorders. However, recent evidence indicates that B cells can also be essential for suppressing unwanted autoaggressive T cell responses, and therefore, a more careful evaluation of which types of autoimmune disorders this therapy should be utilized for, and at which phases of disease this therapy should be applied, is necessary. In this issue of the JCI, Matsushita et al. report that the timing of this therapy is critical for the management of EAE, a mouse model of human MS (see the related article beginning on page 3420). The results suggest the existence of two opposite actions executed by B cells during the course of autoimmune pathology; CD1dhiCD5+ regulatory B cells suppress EAE induction, whereas B cells are required for the expansion of autoantigen-specific T cells during disease progression. Given the existence of such regulatory B cells in humans, these findings not only resolve previously unexplained contradictions with respect to the outcome of B cell–depleting therapy but also provide insight into the best regimen for this treatment approach.