The outcome in children with acute lymphoblastic leukemia has improved significantly over the past four decades. Current therapy results in event-free survival exceeding 80% for most patients. The development of risk-adapted therapy based on characteristics of the child (age), leukemia (leukocyte count, acquired genetic characteristics) and early response to therapy allows dose intensification for children with higher-risk disease. Much less attention has been given to the role of host variability (pharmacogenetic polymorphism) in determining outcome. This review discusses literature reports in this area and describes some of the challenges facing the field as it moves forward.Polymorphisms in many different metabolic pathways have been demonstrated in single gene studies to influence the outcome of acute lymphoblastic leukemia. Challenges arise in establishing the generalizability of observations and interpreting complex gene-gene interactions in multigene pathways. Recent studies also illustrate the importance of correlation of clinical associations with biological mechanisms.Despite significant progress in the treatment of childhood acute lymphoblastic leukemia, therapy is still unsuccessful in 20% of patients. Further knowledge of and insight into the role of host genetic polymorphisms will improve the results by integrating pharmacodynamic and pharmacogenomic studies in individualizing therapy for children with acute lymphoblastic leukemia.