The armamentarium for the treatment of rheumatoid arthritis (RA) includes several classes of therapeutics that induce symptomatic relief and reduce disease activity. The early addition of disease modifying antirheumatic drugs (DMARD) is now the standard of care in treatment. Methotrexate (MTX) is a cornerstone of contemporary management of RA, and the treatment paradigm for RA includes the early use of MTX and combination DMARD. Unfortunately, second-line treatments alone or in combination rarely induce complete disease remission. Advances in the understanding of the pathogenesis of RA have opened the way for more directed therapy, and new therapies that target the cytokine tumor necrosis factor alpha (TNF-alpha) have demonstrated rapid action and substantial benefit with few adverse effects. This article discusses the pivotal role of MTX in combination with DMARD. The use of leflunomide and cyclosporine as single agents and with MTX is evaluated. The role of TNF-alpha antagonism in the treatment of rheumatologic illnesses is examined, with particular attention to etanercept, a recombinant human TNF receptor (p75)-Fc fusion protein, and infliximab, a chimeric TNF monoclonal antibody (CA2). Data on the efficacy and toxicity of etanercept and infliximab are summarized, including their use in combination therapy with MTX.