A number of studies show the efficacy of methotrexate (MTX) for rheumatoid arthritis (RA) in general. However, is there any reason to single this drug out for early RA? Mechanistically, it probably works differently in RA than in cancer, at least in part. Thus, in addition to dihydrofolate reductase-related effects, MTX inhibits aminoimidazocarboxamide transformylase, decreases leukotriene B4 production, and increases adenosine release at concentrations achieved with low-dose MTX regimens. Clinically, it is well tolerated over relatively long periods. Further, a recent meta-analysis of radiology studies shows that MTX compares favorably with intramuscular gold and is better than azathioprine. Toxicity remains a concern in treating early RA, particularly as pulmonary "hypersensitivity reactions" continue (1% to 7.6%), infections (both fungal and perioperative) are documented, and more cirrhosis is found. With all of the above in mind, the use of MTX seems reasonable but not necessarily uniformly appropriate and not yet proved for early RA. Studies of MTX in early RA, particularly in combination with other drugs, are only beginning.