Great progress has been made in recent years in the management of patients with autoimmune diseases, such as rheumatoid arthritis (RA). This progress is largely due to the advances in our understanding of cellular and molecular mechanisms involved in the pathogenesis of inflammation and autoimmunity, and the improved knowledge of molecular biology. Immunotherapy has the potential to modify or re-balance the immune system and hence useful in the management of autoimmune conditions. In this review, we first focus on new biotherapies currently developed in clinic for the treatment of RA. We also outline the limitations of such approaches and review perspectives raised by the current studies on innovative alternatives, such as gene and cell therapy. Immuno-modulation through dendritic cells or mesenchymal stem cells, functionally and / or genetically modified, is under increasing number of investigations and thus will also be discussed. Strategies include the inhibition of pro-inflammatory cytokines, blockade of cartilage-degrading enzymes, inhibition of synovial cell activation or apoptosis of synovial cells and manipulation of the Th1-Th2 cytokine balance. Both viral and non-viral gene transfer vector systems have been used to deliver therapeutic genes systemically or directly to arthritic joints. Animal models of RA have been essential not only for better understanding of the RA mechanisms, but also in serving as basic experimental tools to evaluate candidate gene products with anti-arthritic properties and develop therapeutic strategies. Better understanding of autoimmune mechanisms, advances in vectorology, and combination of immunosuppressive gene / cell therapies promise better immunotherapy for RA in the near future.