There is increasing evidence that the IL-6 family of cytokines and signaling pathways downstream of the common gp130 receptor subunit are important in joint development, in the pathogenesis of both murine and human inflammatory arthritis, and in bone turnover. Although there is some conflicting evidence regarding the role of IL-6, most data from murine models of arthritis favor a proinflammatory role for IL-6. The importance of the IL-6/sIL-6R interaction is becoming apparent. Data from human trials on the effect of IL-6 blockade in RA are encouraging. IL-11 is also of interest because, unlike the other members of the IL-6 family, it appears to have predominantly antiinflammatory effects, raising the possibility of therapeutic use in human inflammatory arthritis. Although the full spectrum of OSM and LIF activities is still to be elucidated, both appear to exert proinflammatory effects within the joints. Although it has been postulated that a few cytokines such as TNF or IL-1 are the primary factors regulating joint inflammation, it is more likely that there is a complex network of cytokines driving pathogenesis. Different key cytokines may be controlling inflammation in the various animal models and genetic strains, and in individual patients with RA at different time points in the disease. Cytokine antagonists provide great clinical promise, and small molecules that inhibit cytokine signaling will provide a new generation of antirheumatic drugs. Our real-world clinical challenge will be to match targeted therapy to the individual patient.