The evidence coming from the different experimental approaches reviewed in this article strongly supports the hypothesis that RA is T-cell driven at all stages of the disease. Although the effector phases responsible for the events that lead to joint destruction involve several different cell types, cytokines, and other mediators, T cells still direct operations behind the scenes. Direct experimental proof of this proposition in patients is still lacking, but the development of nondepleting modulating CD4 monoclonal antibodies may provide new tools to test this hypothesis. In this respect, it is encouraging that using one such reagent, we have recently shown that not only did the activity of the disease improve but, more importantly, the inflammatory indices and production of non-T-cell cytokines were reduced. This is not to dissimilar from the results of experiments described in animals, where by blocking synovial T cells, the production of IL-1 beta and TNF alpha could be decreased by more than 90%. From this perspective, it may be predicted that by modulating T cells in the joint, it is possible to achieve our ultimate goal of permanently switching off the disease.