MTX is still considered the anchor drug among the disease-modifying antirheumatic agents, and it is widely accepted as first line treatment in the management of rheumatoid arthritis (RA). The ultimate therapeutic goal in treatment of RA is remission or at least low disease activity and this goal may not always be achieved with MTX monotherapy. Over the last two decades drug combinations based on MTX have been used increasingly to treat patients with RA. Combination DMARD therapy may be used initially or in a step-up strategy after MTX monotherapy in patients with persistently active disease on monotherapy. Many different MTX based combination regimens have been studied. Frequently used combinations on an MTX background include leflunomide, cyclosporine, azathioprine, sulfasalazine, gold and hydroxychloroquine. In conclusion, the use of MTX in combination with other DMARDs may still represent a valuable therapeutic option in patients who fail to DMARD monotherapy or in whom combination therapy is considered initially. However, in patients at risk for rapid radiographic progression, the early use of biologics has to be considered.