Fractalkine is a CX3C chemokine that exists in both membrane-bound and soluble forms. Interaction between fractalkine and its unique receptor (CX3CR1) induces cell adhesion, chemotaxis, crawling, “accessory cell” activity, and survival. The serum level of fractalkine is elevated in patients with rheumatoid arthritis (RA) and is correlated with disease activity. Peripheral blood CD16⁺monocytes and a subset of T cells express CX3CR1, while fractalkine is expressed on fibroblast-like synoviocytes and endothelial cells in the synovial tissue of patients with RA. Fractalkine expression is enhanced by tumor necrosis factor-α and interferon-γ, and it promotes the migration of monocytes, T cells, and osteoclast precursors into RA synovial tissue. Fractalkine also induces the production of inflammatory mediators by macrophages, T cells, and fibroblast-like synoviocytes. Moreover, fractalkine promotes angiogenesis and osteoclastogenesis. In an animal model of RA, arthritis was improved by the abrogation of fractalkine. Recently, a clinical trial of an anti-fractalkine monoclonal antibody for the treatment of RA commenced in Japan. We review the multiple roles of fractalkine in the pathogenesis of RA and its potential as a therapeutic target for this disease.