A brief review of the pharmacology of methotrexate is presented, and the rationale for the administration of high-dose methotrexate and the necessity of a folinic acid rescue to prevent methotrexate toxicity are discussed. Critical factors concenrning the use of this therapy, as well as unusual toxicities associated with the use of high-dose methotrexate, are presented. Several drug-and patient-related variables which may affect the toxicity of this dual drug administration are discussed to better enable pharmacists to monitor patients receiving this form of therapy. High-dose methotrexate with folinic acid rescue has improved the therapeutic index of methotrexate. The optimal dosage and duration of the two agents are yet to be determined.