Rheumatoid arthritis (RA) has a prevalence of approximately 1%, making it the most common inflammatory rheumatic disease. The outcome for RA patients has significantly improved during recent years. Factors include the introduction of new therapies such as tumor necrosis factor (TNF)-blocking agents and new treatment strategies, especially early and aggressive therapy, including combinations of several disease-modifying antirheumatic drugs (DMARDs). However, only 60-70% of RA patients respond to treatment with a TNF-blocking agent. In addition, most of these patients show only a partial response according to ACR20 criteria. Therefore, to ameliorate painful joint inflammation and prevent disability in RA patients, new treatment principles and more intelligent combination therapies are urgently needed. Interestingly, the strategy of switching patients who no longer respond to one of the TNF blockers to another has often turned out to be effective. Areas of ongoing research include combining TNF-blocking agents with DMARDs other than methotrexate. Also, several new biologics are being tested in clinical trials that promise to soon enhance the therapeutic armamentarium to fight RA. These biologics' mechanisms of action feature blockade of T cell costimulation by a CTLA4Ig fusion protein (abatacept); blockade of interleukin (IL)-6 signaling with an antibody to the IL-6 receptor (MRA); neutralizing IL-15 by a monoclonal antibody; and targeting B cells with an anti-CD20 antibody (rituximab). Other therapeutic approaches, such as blockade of chemokine receptors, adhesion molecules, complement components, and transcription factors regulating the inflammatory response, appear promising; however, they still need careful evaluation in placebo-controlled clinical studies.