Methotrexate (MTX) is well-established as the "anchor drug" for patients with rheumatoid arthritis (RA), to be used early and aggressively, with higher long-term effectiveness, tolerability, and safety than any other disease-modifying antirheumatic drug (DMARD). However, about 20% to 40% of patients experience incomplete responses to MTX and require further therapy, with options including other non- biologic DMARDs, low dose glucocorticoids, and biologic agents. Non-biologic DMARDs in combination with MTX may provide similar efficacy to a biologic agent in clinical trials, with fewer adverse events and lower costs. This re- view presents a summary of 21 clinical trials documenting the efficacy and safety of MTX in combination with other non-biologic DMARDs.