In 2011, the Agency for Health Care Research and Quality (AHRQ) published a systematic review on the comparative effectiveness of disease-modifying anti-rheumatic drugs (DMARDs) used to treat adults with rheumatoid arthritis (RA). The publication was an update to a 2007 report. A total of 258 published articles were used in the AHRQ review to compare the effectiveness of corticosteroids, and oral and biologic DMARDs in the treatment of RA. Head-to-head studies and prospective cohort trials were used to compare one drug to another in determining efficacy and effectiveness. AHRQ compiled this report in an attempt to summarize and integrate the available data for clinicians to make evidence based practice decisions for their patients since there is limited consensus among the medical community regarding the comparative effectiveness of drugs used to treat RA. The report reveals there is still much research to be done concerning the side effects of these agents and their influence in different patient subgroups. To: (a) utilize review findings to make diagnostic and treatment management decisions in clinical practice, (b) inform clinicians on the findings from the updated AHRQ's 2011 comparative effectiveness review on drug therapy for RA in adults, and (c) identify shortcomings in the current research and future directions revealed by the report. Rheumatoid arthritis is a major public health burden. The 2011 updated AHRQ report includes several new medications approved by the FDA since 2007. The review includes 31 head-to-head randomized clinical trials (RCTs), 1 head-to-head nonrandomized controlled trial, 44 placebo controlled trials, 28 meta-analyses or systematic reviews, and 107 observational studies. Most of the studies used for the comparative analysis are of fair quality with an insufficient to moderate strength of evidence assigned to the findings (Table 1). A mixed treatment comparisons (MTC)meta-analysis from the AHRQ report found that the biologic etanercept has a higher probability of improvement in disease activity compared with other biologic DMARDs, but the MTC findings have a low strength of evidence and caution is recommended in the interpretation of this weak evidence. For patients with early RA, limited evidence precludes conclusions about the superiority of one combination therapy versus another. The data are also inconclusive for comparisons of therapeutic similarity among oral DMARDs including the limitation created by differences inmethotrexate (MTX) dosing across trials. Extensive clinical experience over the years support the preferred use of MTX in most patients versus other oral DMARDs as well as its use in multidrug regimens, whereas there is little data on the use of oral DMARDs in combination with biologic agents. The review does not support a specific biologic DMARD over another due to the lack of head-to-head trials comparing these agents using validated RA outcome measures. The data show that the majority of biologics have approximately the same efficacy except for anakinra, which was found to be less effective. The biologic and oral DMARDs are similar in overall tolerability, but several studies suggest that adverse events are more common with biologic DMARDs versus oral DMARDs. Based on limited evidence, the oral DMARDs do not appear to have an increased risk of severe adverse events including cardiovascular events and cancer. Although most studies also found no increased risk of cardiovascular events or cancer with the biologic DMARDs, cohort studies show an increased risk of heart failure with adalimumab, etanercept, and infliximab compared with oral DMARDs. The updated AHRQ review synthesizes the current literature on therapies used for the treatment of RA in adults. The investigators are also able to identify pertinent research gaps in the literature that can be addressed with future research.