Gene therapy offers novel possibilities for the treatment of rheumatoid arthritis. Present research is directed toward harnessing gene transfer technology to deliver genes whose products possess antiarthritic properties; the current emphasis is on transferring genes encoding secreted proteins. Genes may be delivered locally to individual diseased joints or systemically to extra-articular sites where the secreted gene products may enter the circulation. Local delivery is more laborious and unlikely to address systemic components of rheumatoid arthritis but should avoid side effects. Either ex vivo or in vivo strategies may be used to deliver the genes to the target tissues. Ex vivo techniques are more cumbersome but safer, because all genetic manipulations occur outside the body and cells may be extensively screened prior to implantation. A variety of vectors, including retrovirus, adenovirus, herpes simplex virus, and liposomes, as well as naked DNA, have been tested for their ability to deliver genes to joints. At the present stage of vector development, adenovirus seems best suited for in vivo gene delivery to synovium, but several authors have noted an inflammatory response, resulting in loss of gene expression. Ex vivo gene transfer using a retrovirus encoding human interleukin-1 receptor antagonist has succeeded in obtaining high intra-articular transgene expression with promising antiarthritic effects in animal models. Based on these data, the first human gene therapy trial for arthritis has been approved by the US Food and Drug Administration and will begin shortly.