Methotrexate is the most commonly used drug in the treatment of rheumatoid arthritis, although 30-40% of patients fail to adequately respond. An accurate method for measuring methotrexate polyglutamates, the stable active metabolite of methotrexate, has recently been described. The objective of this review article is to determine if clinical use of this measurement would improve methotrexate efficacy, or decrease adverse reactions. Additionally the pharmacologic rationale for this test is discussed. Although methotrexate response improves at higher methotrexate polyglutamate levels, there is no absolute correlation of level with effect. Moreover, overlapping methotrexate polyglutamate levels between clinical responders and nonresponders limits the clinical utility of this measurement.