Methotrexate, a folic acid antagonist, is used extensively not only for the treatment of cancer but also for the treatment of rheumatoid arthritis, psoriasis, and autoimmune disease and for the prevention of graft-versus-host disease after transplantation. The drug is also used as an abortifacient.¹,² Other folate antagonists are used to treat bacterial infections (trimethoprim), malaria (pyrimethamine), and Pneumocystis carinii infection (trimetrexate with leucovorin).³,⁴ As with other drugs used to treat infectious diseases or cancers, the development of resistance limits the effectiveness of these folate antagonists. An understanding of the mechanisms of resistance to this class of drugs is . . .