Recent advances in the understanding of the pathophysiology, aggressive treatment, and early detection of rheumatoid arthritis (RA) have changed the clinical, pathologic, and functional outcomes in patients with RA. Early aggressive treatment of RA has now become the norm in clinical practice rather than the use of the traditional pyramid approach of the last half of the twentieth century. Early treatment with monotherapy of traditional disease-modifying antirheumatic drugs (DMARDs) or biologics, combination traditional DMARD therapy and, especially, combination of biologic therapy and methotrexate, have revolutionized the treatment of RA, producing significant improvement in clinical, radiographic, and functional outcomes not seen previously. For the individual patient, we still cannot determine which medication or combination of medications will give the most complete response. There have been a number of recent, well-designed clinical trials that have tried to answer this question. Herein we review the evidence-based medicine that addresses these issues.