Acute lymphoblastic leukemia in childhood has shown remarkable improvements in outcome over the past decades. This achievement was the result of better patient risk assessment, intensification of treatment, appropriate use of BM transplantation, and improved supportive therapies. Among risk factors, early response (originally morphologic and today minimal residual disease) has acquired a prominent role. The predictive value of minimal residual disease evaluation as a measurement of in vivo drug resistance opened new perspectives for its use in clinical evaluation to determine a risk-based treatment and as a potential surrogate end point for efficacy. More recently, detailed genomic analyses of childhood acute lymphoblastic leukemia have increased our knowledge in this disease. It is likely that this will lead to further improvement of risk assessment and stratification to targeted therapies. Leukemic subsets defined on the basis of biological mechanisms and driver mutations will be ever smaller. To facilitate continued progress, this new scenario will raise methodological issues in study design and the need for collaboration across large, well-characterized patient populations.