Methotrexate is now the disease-modifying antirheumatic drug prescribed most frequently for the treatment of rheumatoid arthritis. Methotrexate is an antifolate that inhibits methylation reactions and reactions of amino acid, purine and pyrimidine metabolism. Toxic manifestations of methotrexate administration for rheumatoid arthritis (at relatively low doses compared with those used in cancer chemotherapy) include cytopenias, gastrointestinal intolerance, liver disease, pulmonary injury, central nervous system dysfunction, skin rashes and nodulosis. Delayed wound healing and increased risk for infections with opportunistic organisms also occur. Some of these toxic manifestations respond to supplementation with folates [folic acid or folinic acid (calcium folinate)]. The folate status of patients has been shown to be impaired after prolonged treatment with methotrexate, and poor baseline folate status is an independent risk factor for subsequent toxicity. Numerous studies have now documented that folic acid, even in high doses, and moderate doses of folinic acid are beneficial in preventing methotrexate toxicity without affecting efficacy. In this article we present-guidelines and rationale for monitoring methotrexate therapy, and guidelines for folate supplementation during methotrexate therapy for rheumatoid arthritis. It is our recommendation that folic acid should be empirically supplemented in all patients at the initiation of methotrexate therapy. This regimen is associated with a high benefit:risk ratio and is likely to be cost effective.