B cells and B cell-derived autoantibodies play a central role in the pathogenesis of many autoimmune diseases. Thus, depletion of B cells via monoclonal antibodies such as Rituximab is an obvious therapeutic intervention and has been used successfully in many instances. More recently, novel therapeutic options targeting either the autoantibody itself or resetting the threshold for B cell activation have become available and show promising immunomodulatory and anti-inflammatory effects in a variety of animal models. The aim of this review is to summarize these results and to provide an insight into the underlying molecular and cellular pathways of these novel therapeutic interventions targeting autoantibodies and B cells and to discuss their value for human therapy.