For some time, B cells have been considered as passive actors, exclusively depending on T cell conductors that provide them with instructions to engage in antibody secretion. With further investigation, however, it became evident that B cells can exert a number of antibody-independent functions, capturing and concentrating antigen for presentation, producing cytokines, influencing T cell and dendritic cell responses, contributing distinct functions during the immune response, affecting lymphoid tissue structures, and, even participating in tissue repair. Because of their multiples functions, B cells are currently recognized to play a key role in a variety of antibody-, and T cell-mediated autoimmune diseases, including lupus, rheumatoid arthritis, type-1 diabetes and multiple sclerosis. This recent insight led to novel immuno-intervention strategies that target B cells, with beneficial effects in patients. While such novel therapeutic bio-drugs are being introduced into the clinical arena, research intensifies in order to identify novel targets and strategies whose ultimate goal is to knock out specifically pathogenic B cells, and to amplify the numbers and the activity of cells endowed with regulatory functions.