B lymphocyte involvement in systemic lupus erythematosus has been recognized for several decades, mainly in the context of autoantibody production. Both mouse and human studies reveal that different types of antibody responses, as well as antibody-independent effector functions can be ascribed to distinct subpopulations (subsets) of circulating B cells. Characterizing human B cell subsets can advance the field of autoimmunity even further by establishing B cell signatures associated with disease severity, progression, and response-to-treatment. For this purpose, we have developed specialized B cell reagent panels for multiparameter flow cytometry, and combine their use with advanced bioinformatics strategies that together will likely be advantageous for improving the characterization, prognosis, and for possibly improving treatment regimens of chronic inflammatory diseases such as lupus.