EFS for children with ALL continues to increase and is predicted to reach 90% with current therapy. Better understanding of leukemia cell biology and pharmacogenetics has led to the design of more effective treatment and also refined the prognostic features associated with a poor outcome. ALL characterized by the translocation t(9;22) or t(4;11), or by a hypodiploid karyotype or by an incomplete response to induction therapy is likely to relapse. SCT for ALL is largely used to treat patients failing primary chemotherapy but is selectively included as part of initial therapy for children at high risk for relapse. If SCT is going to become the primary therapy for children with ALL in first remission, the regimen-related mortality must approach 0%, and the risk for severe acute and chronic GVHD should be less than 5%. Salvage therapy after ALL relapse remains the major indication for SCT. The time required to find a suitable match has led to the use of cord blood and haploidentical related donors as stem cell sources. For children who relapse, SCT is likely to remain the principal option to promote survival. Efforts to reduce both the risk of relapse and the transplant regimen toxicity, both immediate and delayed, must continue.