Increasingly vigorous chemotherapy of cancer including primary and metastatic central nervous system disease has resulted in prolonged good-quality survival. However, there has been an associated increase in neurotoxicity from both radiation therapy and chemotherapy. All classes of chemotherapeutic agents contain drugs that are potentially neurotoxic, often only at high doses. Mechlorethamine, the first nitrogen mustard, is not neurotoxic at conventional dosage, but at high doses, it may produce both an acute and a delayed encephalopathy. Methotrexate administered intrathecally often induces reversible aseptic meningitis, but chronic administration, either intrathecally or high-dose intravenously, may produce fatal leukoencephalopathy. 5-Fluorouracil at high dosage may cause cerebellar ataxia, but may also do so at low dosage when combined with thymidine infusions. Cytosine arabinoside at high dosage may also produce cerebellar ataxia. Vincristine produces a peripheral neuropathy, and less commonly causes both autonomic and cranial neuropathy. The enzyme L-asparaginase can produce a dose-related reversible encephalopathy. BCNU, now the mainstay of glioma chemotherapy, may combine with radiation to produce long-term cerebral atrophy. Both intracarotid and high-dose intravenous BCNU administration may cause encephalopathy. Several other chemotherapeutic agents have also been reported to cause neurotoxicity under certain circumstances.