MTX has been demonstrated to be one of the most effective agents in current use for the treatment of patients with active RA who have failed other approaches. Therapy must be individualized to achieve an optimal efficacy/toxicity profile. The drug is a potent steroid-sparing agent which is a factor of marked significance in this patient group. Although cellular activity is well described, many unanswered questions about its absorption, target cell population, and mechanism of action remain. More information is needed about the true incidence of long-term toxicities to be able to better address the all important issue of when to use MTX in the treatment of RA. Research efforts, including studies of immunologic parameters over time, are needed to achieve a better understanding of the drug's mechanism of action. Lastly, the reasons for the plateau in clinical response to MTX should be explored to devise strategies to enhance and sustain the effects of this already potent drug.