While major advances have been made in the treatment of acute leukemia, complications of therapy are significant. One of the most worrisome complications is the neurotoxicity which is related to both central nervous system prophylaxis (cranial irradiation and intrathecal therapy) and systemic chemotherapy. The clinical manifestation(s) of neurotoxicity may be acute or delayed, and may range in severity from mild headaches and peripheral neuropathies, to progressive dementia, coma, and death. Early recognition of treatment-related neurotoxicity is important since this may permit amelioration of otherwise irreversible neurological sequelae in some patients. We review the clinical, physiological and pharmacological spectrum of the neurotoxicity which is associated with irradiation and chemotherapy, and offer recommendations for monitoring, evaluating and treating patients with potential or proven neurotoxicity.