Childhood acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. Studies in ALL have been a model for clinical and basic research beyond pediatric hemato-oncology. As a result of sustained and well-organized research efforts since the early 1960s, childhood ALL now can be successfully treated in about 80% of patients by the application of intensive combination chemotherapy regimens, which in specific patient subgroups may need to be supplemented with radiation therapy and/or hematopoietic stem cell transplantation. Triggered by the observation of specific clinical presenting features, biological characteristics, and early treatment response being associated with treatment outcome, therapy intensity in contemporary ALL protocols is adjusted according to prognostic factors predicting the risk of relapse. While the goal of effective therapy for the majority of children with ALL has been achieved, significant numbers of patients still die due to recurrent disease or the toxicity of treatment. Thus, future research must extend our molecular understanding of leukemia and host factors in order to even more specifically identify the mechanisms underlying the differences in treatment response and outcome, and to finally address the therapeutic needs of the individual child.