Despite major progress in the treatment of rheumatoid arthritis (RA), strong unmet medical need remains, as only a minor proportion of patients reach sustained clinical remission. New approaches are therefore necessary, and include manipulation of regulatory T cells, which might be able to restore the disturbed immune system and could even lead to a cure if this restored regulation were to prove sustainable. Logistical and conceptual problems, however, beset this attractive therapeutic approach, including difficulties with ex vivo expansion of cells, specificity of targeting and the optimal time point of administration. Therefore, alternative avenues are being investigated, such as targeting B-cell effector functions and newly identified proinflammatory cytokines. On the basis of success with B-cell depleting therapy using anti-CD20 agents, further treatment modalities are now exploring direct or indirect interference in B-cell-mediated immunity with the use of agents directed against other B-cell surface molecules. Novel approaches target intracellular B-cell signalling and regulatory B cells. New cytokine-directed therapies target important proinflammatory mediators such as GM-CSF, new members of the IL-1 family, IL-6 and its receptor, IL-17, IL-20, IL-21, IL-23 as well as synovium-specific targets. This article reviews these emerging cell and cytokine targets with special focus on biologic agents, some of which might reach the clinic soon whereas others will require considerable time in development. Nevertheless, these exciting new approaches will considerably enhance our repertoire in the battle against this potentially devastating disease.