Because it plays a central role in the immunopathogenesis of rheumatoid arthritis (RA), TNF-alpha is an attractive target for immunomodulatory therapy. In a number of rigorous studies, monoclonal antibodies (mAb) specific for TNF-alpha have proved efficacious in patients with active RA. Data from these studies and issues related to mechanisms of action, potential toxicity, and future directions for this novel therapeutic approach are considered in this review.