Overproduction of tumor necrosis factor-alpha (TNF) plays a key role in the pathogenesis of rheumatoid arthritis (RA) and other chronic inflammatory diseases. In RA, excessive production of TNF-alpha can drive synovial inflammation and proliferation as well as degradation of articular cartilage and bone. The importance of TNF-alpha in these mechanisms is supported by the results of clinical trials. In these studies, treatment with etanercept and infliximab, two recently approved TNF-alpha inhibitors, has been shown to significantly decrease the signs and symptoms of joint inflammation and slow the progression of radiological joint damage. Although TNF-alpha inhibitors have had acceptable toxicity in clinical trials, commercial use of these agents has produced growing concerns about the potential risk for opportunistic infections, most notably the reactivation of latent tuberculosis. The TNF-alpha inhibitors stand as a powerful example of the therapeutic potential of a targeted biological agent. Longer-term clinical experience with these cytokine antagonists will illuminate their optimal use in RA and other rheumatic diseases.