Therapy for prevention of central nervous system (CNS) leukemia has had a dramatic effect on disease-free survival in children with acute lymphoblastic leukemia (ALL). Now, a majority of children may be in complete remission indefinitely, having completed therapy years ago. Unfortunately, some of these long-term survivors have residual neurologic dysfunction, varying in severity from the not uncommon occurrence of mild intellectual deficit to the fortunately rare instance of debilitating leukoencephalopathy. To help identify inciting factors and ultimately render CNS prophylaxis less neurotoxic, this article attempts to categorize the types of neurotoxicities reported in patients treated with methotrexate (MTX) and ionizing radiation. A variety of clinical syndromes are described and related temporally to these treatment modalities. Analyzed in this way, combinations including CNS irradiation appear to be the most neurotoxic. The safest methods are the single modalities, of which high-dose iv MTX may be the least neurotoxic.