Rheumatoid arthritis (RA), the most common autoimmune disease, is characterized by persistent synovitis and systemic inflammation. Genetic predisposition as well as autoantibodies and environmental factors, such as smoking, are associated with an increased risk of RA. Traditionally RA has been treated with disease modifying anti-rheumatic drugs (DMARDs) but in the last 15 years or so the introduction of biological response modifiers has revolutionized the treatment of RA. Among these anti-tumor necrosis factor (TNF) agents were the first to be successfully used in treating RA. The goal in treating RA is to induce remission or very low disease activity; remission is now accepted as the ultimate therapeutic goal by adoption of a “treat to target” strategy to achieve tight disease control. Therefore early diagnosis, as well as immediate intervention, are of the utmost importance. This review of the role of TNF in RA pathogenesis describes the mechanisms of action of currently used anti-TNF agents and the adverse events and safety of these drugs. Guidance on the use of anti-TNFs during pregnancy and prior to surgical procedures is also discussed. The intense efforts currently being made to identify biomarkers of response to anti-TNF therapy and recent progress in defining genetic predictors of response using genome- wide association studies (GWAS) are covered. However, so far, none of these studies have been translated into clinical application. The development of biosimilars or follow-on biologicals is also discussed and the first reported study of a biosimilar, involving a multicenter study of an etanercept biosimilar, Etanar, is described.