Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that causes significant morbidity and mortality. RA patients should be started with DMARD as early as possible and among multiple DMARD methotrexate (MTX) is considered the anchor drug and should be used first. However, even use of MTX often fails to control disease activity and to prevent structural damage and, thereby, more effective treatment strategies are needed. 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. Biologics targeting TNF-alpha with MTX, have revolutionized the treatment of RA, producing significant improvement in clinical, radiographic, and functional outcomes not seen previously. Herein I review the evidence-based medicine that addresses these issues and document an era of anti-cytokine therapeutics which is beginning to emerge.