The pathophysiology of rheumatoid arthritis (RA) is primarily driven by proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha. Several biological agents have been identified that effectively block the activity of these cellular messengers, and administration of these agents to animal models of RA and human patients has been found to have therapeutic benefit. The application of gene therapy for the treatment of RA and other articular diseases is being explored to overcome current limitations with delivery of therapeutics to joint tissues. To date, laboratory research has focused on two main areas: (1) evaluation of gene delivery approaches and (2) identification of therapeutic gene products. Considerable progress has been reported with the use of local gene delivery to synovial cells by both in vivo and ex vivo methods and by systemic administration of gene delivery vectors via the circulation. Gene products that have therapeutic efficacy in animal models of RA include: IL-1 receptor antagonist, soluble IL-1 receptor I, soluble tumor necrosis factor receptor II, viral IL-10, and transforming growth factor beta, among others. The success of these laboratory studies has led to the implementation of a Phase I clinical trial to asses the safety and feasibility of using gene therapy in the treatment of RA.