Methotrexate (MTX) is an antifolate that has been in use for the treatment of rheumatoid arthritis (RA) since the early 1980s. Its efficacy has been clearly documented [1-4] and its administration early in the course of the disease is now generally accepted [5]. Side-effects from low weekly pulse MTX have been reported [1-6] and it was our initial experience that toxicity, rather than lack of efficacy, was the major factor limiting its clinical use [7]. However, when compared with other disease-modifying antirheumatic drugs, its toxicity appears to be comparable to that of antimalarials [8, 9]. The purpose of this paper is to discuss the possible mechanisms responsible for toxicity due to MTX used at low weekly pulse doses for the treatment of RA, as well as the different toxic manifestations reported in the literature.