IFN-beta is a cytokine with pleiotropic effects and is expressed in rheumatoid synovial tissue. Based on in vitro work and experiments in animal models of rheumatoid arthritis (RA), the effects are mainly anti-inflammatory. Of special interest is the ability of IFN-beta to reduce the secretion of TNF-alpha, IL-1 beta, and IL-6, which are all key players in the pathogenesis of RA. At the same time IFN-beta could enhance the production of anti-inflammatory mediators like IL-1 receptor antagonist (IL-1Ra) and IL-10. Treatment of mice and monkeys with collagen-induced arthritis with daily IFN-beta injections resulted in clinical improvement, decreased synovial inflammation, and protection against joint destruction. Similar data were obtained after IFN-beta gene therapy. However, treatment of RA patients with IFN-beta has been unsuccessful so far, presumably due to pharmacokinetic issues. Novel approaches leading to constitutive IFN-beta production at the site of inflammation may be required to induce clinical efficacy in patients.