Multiple sclerosis (MS) is a chronic inflammatory neurological disease of the CNS that goes along with demyelination and neurodegeneration. It is probably caused by an autoimmune response against the CNS, which emerges from the interplay of genetic and environmental factors. Although major progress has been made in the treatment of MS, it is still the leading cause for acquired nontraumatic neurological disability in young adults. Several therapeutic agents have been approved for the treatment of relapsing-remitting MS (RRMS), aiming at the reduction of relapses and a delay in disability progression. Three therapeutic monoclonal antibodies targeting CD20-positive B cells (rituximab, ocrelizumab and ofatumumab) were investigated in MRI-based Phase II and Phase III trials in RRMS, providing consistent evidence for a disease-ameliorating effect of B cell depleting therapies in MS. Here, we discuss the role of B cells and review current and future therapeutic approaches to target B cells in MS.