Multicenter trials in children and young adults using second-generation CD19-targeted chimeric antigen receptor (CAR) T cells have shown dramatic levels of remission in patients with multiply relapsed/refractory disease (80% to ≥90%). Early results in adult trials have also shown significant responses, and strategies aimed at mitigating toxicities associated with the therapy have improved tolerability. Therefore, if available, CAR T-cell therapy deserves consideration for salvage of children and adults with B-lineage acute lymphoblastic leukemia (B-ALL) who are multiply relapsed, refractory, or relapsed after a previous allogeneic transplantation. For patients with a first relapse or who have persistent minimal residual disease (MRD) after initial or relapse therapy, treatment with blinatumomab or inotuzumab is reasonable to help patients achieve MRD− remission before definitive therapy with allogeneic hematopoietic cell transplantation (HCT). A number of studies in younger patients using 4-1BB–based CAR T-cell constructs lentivirally transduced into patient T cells and then optimally expanded have resulted in long-term persistence without further therapy. In 1 study using CD28-based CARs in adults, the benefit of HCT after CAR T-cell therapy was not clear, because a group of patients experienced long-term remissions without HCT. These data suggest that CAR T-cell therapy may be able to substitute for transplantation in many patients, avoiding the risks and long-term consequences of HCT. With this is mind, and with emerging data better defining ways of enhancing CAR T-cell persistence and avoiding relapse through antigen escape, CAR T cells will have a growing role in treatment of both pediatric and adult B-ALLs in the coming years.