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The overall goal of therapy for patients with rheumatoid arthritis (RA) is to achieve low disease activity or remission and to prevent or control joint damage, prevent loss of function, and decrease pain. However, many patients with RA do not have the disease adequately controlled, and only a minority attain consistent remission. To successfully treat to target, rheumatologists need practical guidance to select monotherapy and combination therapy regimens based on available data. Differences in study design, dosing regimens, and data from defined and specific patient populations pose challenges to clinicians who treat patients with diverse characteristics and needs. Because clinical trial results are not always translated into real-life clinical practice, this article synthesizes evidence from all sources, including meta-analyses of clinical trial data, data from patient registries in RA, and results of pragmatic trial designs. Practical guidance with these strategies is demonstrated using application in patient case scenarios, which will enable rheumatology health care professionals to more easily compare the effectiveness and safety of RA treatment strategies as experienced in real-life practice settings. Combination therapy is important for most patients with RA; however, there remain no clear guidelines for selecting the most appropriate combination strategy.