The hypothesis of rheumatoid arthritis (RA) as a T cell mediated disease has led to the development of numerous therapeutic approaches that target the function of T cells. The development of monoclonal antibodies against the T cell surface molecule CD4 has raised hopes to achieve a major progress in the treatment of RA. However, after encouraging results in early open studies, double blind trials were unable to demonstrate the efficacy of anti-CD4-therapy in RA. There are numerous reasons to explain the failure of this treatment approach. Besides the fact that the T cell hypothesis of RA has repeatedly been challenged, pharmacological problems or an inappropriate selection of outcome criteria have to be considered. The final evaluation of anti-CD4 therapy in RA will be possible only after the testing of newly developed non-depleting anti-CD4 antibodies.