Methotrexate has been reported to be effective in various animal models of arthritis as well as a variety of human disorders without a shared pathogenesis. Reports have emerged of the effect of the drug on lymphocytes, cytokines, leukotrienes, neutrophils, as well as a large variety of intracellular biochemical pathways. At present, it is not possible to identify which of the many possible mechanisms of action are relevant to its action when used in patients with rheumatoid arthritis (RA). More definitive insights may have to await a better understanding of the immunopathogenesis of RA.