The development of successful therapy for most children with acute lymphoblastic leukemia can be attributed to sequential clinical studies that show the importance of combination chemotherapy, sanctuary-specific treatment, and supportive care measures. The relative resistance of acute myelogenous leukemia to chemotherapy led to strategies that include dose-intensified chemotherapy and bone marrow transplantation. The improvement in long-term survival for children with acute leukemia has been gratifying but also has been associated with late effects that underscore the need for careful follow-up and for designing risk-adapted therapies.