Major challenges remain to be overcome to increase the cure rate for acute lymphoblastic leukemia (ALL), especially for middle-aged and older adults. Despite high rates of complete remission (CR), many patients relapse after chemotherapy alone. Dose-intensive therapy and stem-cell transplantation (SCT) have been able to rescue some of these patients. However, many patients presently are being cured using intensive consolidation chemotherapy during first remission (CRI) and at a lower cost and toxicity than with SCT. The use of SCT in CRI should be governed by an assessment of known risk factors. Among younger adults in the prime transplant age group (< 50 years), there is no advantage to allogeneic (allo)-SCT across the board, but it is recommended for those with Philadelphia chromosome-positive (Ph+) ALL or pro-B ALL with t(4;11) and possibly for those with B-lineage ALL and initial WBC counts > 100,000/microL. There is as yet no evidence that allo-SCT can improve the already high cure rate achieved with chemotherapy alone in favorable subsets such as T-cell ALL. There appears to be no advantage to autologous (auto)-SCT over chemotherapy for consolidation of either high-risk or standard-risk patients in CRI. The argument that early use of auto-SCT shortens the duration of treatment and thereby improves the quality of life is not persuasive, as there is little morbidity from maintenance chemotherapy. Patients who receive a modern, intensive multiagent chemotherapy program for CRI but later relapse are unlikely to be cured with additional chemotherapy alone. High-grade multidrug resistance develops rapidly. These patients should undergo allo-SCT if possible. Unfortunately, allo-SCT is available to only a minority of such patients because of the lack of a donor or insurance coverage, or the presence of comorbid conditions or older age. The use of alternative donors (either matched, unrelated donors or partially human leukocyte antigen [HLA] matched family members) is appropriate in this circumstance. Auto-SCT with or without previously used purging methods is ineffective for patients with advanced ALL.