Approximately 90% of the 2,000 children, adolescents, and young adults enrolled each year in Children's Oncology Group acute lymphoblastic leukemia (ALL) trials will be cured. However, high‐risk subsets with significantly inferior survival remain, including infants, newly diagnosed patients with age ≥10 years, white blood count ≥50,000/µl, poor early response or T‐cell ALL, and relapsed ALL patients. Effective strategies to improve survival include better risk stratification, optimizing standard chemotherapy and combining targeted therapies with cytotoxic chemotherapy, the latter of which is dependent upon identification of key driver mutations present in ALL. Pediatr Blood Cancer 2013; 60: 957–963. © 2012 Wiley Periodicals, Inc.