Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that causes significant morbidity and mortality. TNF-alpha plays a pivotal role in the pathological processes of RA by accumulation of inflammatory cells and the self-perpetuation of inflammation, leading to cartilage and bone destruction. Two TNF inhibitors, infliximab, an anti-TNF-alpha chimeric monoclonal antibody, and etanercept, a fusion protein of soluble TNF receptor and Fc portion of immunoglobulin, were marketed in 2003 and 2005, respectively, in Japan. The combinational use of biologics targeting TNF-alpha and methotrexate (MTX) have revolutionized the treatment of RA, producing significant improvement in clinical, radiographic, and functional outcomes not seen previously. Namely, biologics targeting TNF have brought about a paradigm shift in the treatment outcome of RA; i) remission induction and maintenance, ii) suppression of progress of joint destruction, iii) improvement of mortality. Furthermore, recent controlled trials have shown that biologics targeting cell surface molecules on B cells and T cells are effective in RA patients with active disease despite TNF inhibitors. Thus, targeting cytokines and lymphocytes not only expands the array of treatments for RA but also provides important insights into the pathogenesis of this disease. In this review, how to use TNF inhibitors for the treatment of RA will also be discussed from domestic as well as global evidence.