Many cytokines have been described in the synovium in animal models of inflammatory arthritis and in patients with rheumatoid arthritis (RA)(1–7). These small molecules mediate communication between cells, resulting in the attraction of inflammatory and immune cells into the joints and the activation of cells to release products that lead to tissue destruction. The cytokines in the rheumatoid synovium function in a network of overlapping, synergistic, antagonistic, and inhibitory activities. The net biologic response will depend on the balance between multiple factors that are present. This review summarizes some aspects of the cytokines that are involved in the pathophysiology of rheumatoid synovitis and current or potential therapeutic approaches to inhibit the production or effects of these cytokines. The 2 major proinflammatory cytokines, interleukin 1 (IL–1) and tumor necrosis factor alpha (TNF), will be emphasized. Cytokines can be classified according to their main function in the rheumatoid disease process, as presented in Table 1. In this scheme, cytokines are grouped under hematopoietic, growth and differentiation, immunoregulatory, pro-inflammatory, anti-inflammatory, and chemotactic factors. However, it should be emphasized that any cytokine may function under more than one of these categories. Cytokine receptors are classified by their structural similarities, as well as by the use of common molecules of signal transduction. In general, the production of cytokines can be induced by bacterial and viral products, complement split products, immune complexes, fragments of connective tissue proteins, acute-phase proteins, or other cytokines themselves. The mechanisms by which excess production of IL-1 and TNF is stimulated in the rheumatoid synovium remain unclear, but macrophages in the inflamed synovium appear to be the main source. Cytokines bind to specific receptors on cell surfaces, stimulating pathways of signal transduction that lead to increased or decreased transcription. Two signal transduction pathways that may be important in the rheumatoid synovium are the AP-1 pathway and the NF-B pathway (8). The NF-B signal transduction pathway appears to be particularly important in chronic inflammatory diseases, both in mediating the production of IL-1 and TNF and in mediating their effects on target cells after they have bound to cell surface receptors. Stimulating these signal transduction pathways leads to the release from target cells of collagenases and other enzymes, other pro-inflammatory molecules, and more cytokines.