Long-term survival rates in childhood acute lymphoblastic leukemia (ALL) have improved due, in part, to the introduction and subsequent refinements in central nervous system (CNS)-directed therapy. Studies of cognitive, motor, and behavioral functioning, which characterize the patterns and severity of CNS sequelae, are being used increasingly as measurable treatment endpoints. This paper summarizes the advances in CNS-directed therapy derived from Children's Cancer Group randomized therapeutic trials. Results from neurobehavioral outcome studies built upon these trials are also presented. A section of this review is focused on CNS-directed treatments and the neurodevelopmental outcomes of infants diagnosed with ALL, an especially high-risk patient subset. Future studies of neurobehavioral outcome are briefly elaborated in the context of current chemotherapy approaches used in the treatment of childhood ALL.