Tumor necrosis factor-alpha (TNF-alpha) antagonists have rapidly emerged as a valuable class of antirheumatic agents. Etanercept, a dimerized version of the soluble tumor necrosis factor receptor II, and infliximab, a chimeric anti-TNF-alpha monoclonal antibody, are currently approved for the treatment of rheumatoid arthritis (RA) based on their proven beneficial effects in clinical trials. New insights into the role of TNF-alpha in disease pathogenesis have expanded our understanding about the possible mechanisms by which these agents reduce synovial inflammation and inhibit bone and cartilage degradation. The enlarging safety experience has revealed growing concerns about TNF-alpha inhibition and increased risk for opportunistic infection, most notably the reactivation of latent Mycobacterium tuberculosis infection. Recent recommendations have addressed this risk by calling for pretreatment screening for previous exposure to tuberculosis. The success of etanercept and infliximab therapy for RA has prompted the development of other TNF-alpha antagonists and extended the investigation of this therapeutic approach to other inflammatory diseases. TNF-alpha antagonists promise to shape the care of RA and other rheumatic diseases for many years to come.