Methotrexate: MTX（aminopterin）, a folate antagonist was first reported in 1948 to induce temporary remission of acute leukemia of children. In the 1950s, the efficacy of MTX for RA and psoriasis patients was reported. Now, MTX is globally considered as the anchor drug for the treatment of RA because of long-term efficacy and safety. Therefore, MTX is used in more than 70% of RA patients by monotherapy or combination therapy. In Japan, MTX was firstly introduced into the market in 1999, about 10 year behind the approval by FDA in US. However, after high-dose MTX up to 16 mg/week was approved in 2011, MTX has been used more aggressively. Although the recent aggressive treatment with lead to better disease outcome, serious infections and lymphoproliferative disorders（LPD）due to long-term immunosuppression tend to increase, especially in elderly RA patients. This paper reviews the history of the development of MTX as an anti-rheumatic drug.