Cytokines such as TNF-alpha and IL-1beta play key roles in driving the inflammation and synovial cell proliferation that characterize rheumatoid arthritis (RA) joint destruction. It is, therefore, not surprising that therapies for RA have targeted these cytokines. While blockade of TNF-alpha or IL-1beta has been efficacious for many patients with RA, adequacy and maintenance of response are not universal, and increased risk of adverse events such as infection and malignancy remains a concern. Therefore, new targets in the treatment of RA continue to be examined. As interleukin-6 (IL-6) has been implicated in the pathogenesis of RA, blockade of its activity is of both scientific and clinical interest. The basic biology of IL-6, the in vitro animal data supporting its role in RA, and the human trials to date that test the possible efficacy of IL-6-directed therapy for RA are reviewed.