Methotrexate (MTX), an antifolate agent, has been used in the treatment of rheumatoid arthritis (RA) for over two decades. Open clinical studies and short-term, randomized, placebo-controlled studies demonstrate the efficacy of MTX in active RA. Long-term prospective studies, including two of over 7 yr duration, report a sustained response and a corticosteroid-sparing effect. Comparative studies demonstrate superior efficacy to auranofin, azathioprine and cyclosporin A. A highly favourable retention rate with the drug has been noted in large studies from academic and community-based practices. Radiographic studies suggest a slowing of radiographic progression with the compound. MTX has become an accepted and widely used treatment for active RA.