Edatrexate (10-ethyl, 10-deaza-aminopterin; 10-EdAM) is one of a group of compounds developed by substitutions at the N10-position of 4-aminofolate. In phase I and II trials, activity has been seen against non-small-cell lung cancer, breast cancer, non-Hodgkin's lymphoma, and cancer of the head and neck. In preclinical studies, a synergistic effect has been reported when edatrexate is combined with other antineoplastic drugs, and enhanced activity has been seen in two combination-chemotherapy phase II studies in patients with non-small-cell lung cancer. In in vivo preclinical studies, edatrexate has demonstrated antitumor activity against mouse solid and ascites tumors as well as human tumor xenografts. The activity is superior to that of methotrexate and the other antifolates tested. The improved therapeutic index of edatrexate appears to be related to its increased entry into, and polyglutamylation within, tumor cells, and its relative exclusion and rapid elimination from sensitive host tissues, compared to methotrexate. Edatrexate is metabolized in the liver and then excreted mainly in the bile. In clinical trials in cancer patients, the dose-limiting and most frequent toxicity is mucositis. Other side effects are generally mild and include myelosuppression, nausea, vomiting, elevations in SGOT, and macular rash. The responses seen in clinical trials along with preclinical data suggest that edatrexate may be a valuable agent in the treatment of cancer. Studies currently underway include the evaluation of edatrexate in small-cell lung cancer and edatrexate in combination with leucovorin, new vinca alkaloids, and cisplatin.