Despite many years of investigation, there remain many unanswered fundamental questions on the role of B cells in RA. Why is RF found in the sera of 80% of patients with RA and often in other chronic inflammatory diseases? What signals lead B lymphocytes to migrate into the subsynovial lining of joints? Does receptor revision in synovium play a role in the generation of autoantibodies in RA? What is the relative contribution of B-cell inhibition on the salutary effect of medications for RA? Can targeting autoreactive B cells, in conjunction with other therapies, provide therapeutic benefit in RA? We are hopeful that through continued basic, clinical, and translational research, these questions can be answered.