B cells are central pathogenic players in systemic lupus erythematosus and multiple other autoimmune diseases through antibody production as well as antibody independent function. At the same time, B cells are known to play important regulatory functions that may protect against autoimmune manifestations. Yet, the functional role of different B cell populations and their contribution to disease remain to be understood. The advent of agents that specifically target B cells, in particular anti-CD20 and ant-BLyS antibodies, have demonstrated the efficacy of this approach for the treatment of human autoimmunity. The analysis of patients treated with these and other B cell agents provides a unique opportunity to understand the correlates of clinical response and the significance of different B cell subsets. Here, we discuss this information and how it could be used to better understand SLE and improve the rational design of B cell-directed therapies in this disease.