The pharmacokinetics, therapeutic index, neurotoxicities, methods of administration, and dosages of intrathecal methotrexate are reviewed. The intrathecal administration of methotrexate can provide therapeutic concentrations in the cerebrospinal fluid (CSF) without the use of high-dose intravenous methotrexate. Major neurologic complications have been reported to occur in 3--40% of patients following intrathecal methotrexate. The development of neurotoxicity is related to dose, concentration of methotrexate in the CSF, age of the patient, anatomical and physiological abnormalities in the CNS, type of dilutional vehicle, intracranial radiation, and intravenous methotrexate. Substantial evidence is lacking that chemical preservatives and methotrexate breakdown products are risk factors. The use of intrathecal methotrexate is a reasonably safe and effective chemotherapeutic modality when proper administrative techniques are observed.