This article summarizes studies conducted in children with acute lymphoblastic leukemia (ALL) who received intrathecal methotrexate (IT MTX) to prevent or treat central nervous system (CNS) leukemia. To better understand the pharmacologic requirements of intrathecal chemotherapy directed against CNS leukemia, this report begins with a review of the pathophysiology of CNS leukemia and the clinical aspects of this disease manifestation that influence IT MTX therapy. The pharmacokinetics of IT MTX are then presented and the review is concluded with observations on the importance of the dosage regimen.