Methotrexate is a chemotherapeutic and anti-inflammatory agent used in cancers, hematologic and rheumatologic diseases, binding to Dihydrofolate Reductase (DHFR) as a competitive inhibitor, modulating inflammation by inhibition of transmethylation reactions.^1,2 Life threatening hypersensitivity reactions (HSRs) have been reported with methotrexate. ^3,4,5 Alternative treatments result in suboptimal outcomes/ death due to cancer progression. Drug desensitization enables patients to continue treatment, preventing anaphylaxis by inducing a temporary tolerance.³ We report a case of a child with Acute B-cell Lymphoblastic Leukemia who successfully tolerated methotrexate desensitization, and subsequently weaned to a weekly oral challenge. He is now taking weekly methotrexate without any reactions.