The central nervous system (CNS) has long been recognized as a site, indeed a sanctuary, for leukemic cells. Although few (<5%) patients with acute lymphoblastic leukemia (ALL) actually present with overt CNS leukemia, without prophylactic CNS-directed treatment, over 50% will develop CNS disease. However, with modern CNS prophylaxis, the incidence of CNS relapse has been reduced to 6% or less. Although great progress has been made, we continue to struggle with management of CNS leukemia. This commentary will address issues of CNS leukemia treatment at diagnosis and at relapse. Topics that will be addressed include (1) CNS 2 status at diagnosis-definition and treatment; (2) CNS leukemia at diagnosis--treatment with radiation therapy; (3) isolated relapse of leukemia in the CNS--treatment of early and late relapse; and (4) opportunities for future research in CNS relapse of ALL.