An understanding of the pathology of central nervous system (CNS) leukemia has evolved slowly. Observations in the 19th century clearly established CNS leukemia as a disease involving the leptomeninges. Although infiltration of the leptomeninges by leukemic cells remains the principal CNS lesion in patients with this disease, other histopathologic changes have become evident with the development of antileukemic therapy. During the early years of chemotherapy, as patient survival increased, the effects of chronic meningeal leukemia, e.g., increased intracranial pressure, became prominent. Only recently, following effective control of CNS leukemia with chemotherapy and irradiation, did it become clear that current methods of treatment can produce neurotoxic effects. Two specific examples are leukoencephalopathy and mineralizing microangiopathy, both apparently induced by the effects of radiation on the microvasculature. Only through careful prospective studies can the consequences and actual incidence of these two lesions be determined. These results will permit sounder judgments of whether the risks of CNS radiotherapy outweigh the known benefits.