Despite great progress in the curative treatment of leukemia in pediatrics, current therapies are associated with multiple toxicities and the prognosis after relapse is guarded. Novel approaches are needed to overcome resistance to standard therapy and decrease adverse effects. The efficacy of allogeneic stem cell transplantation and the demonstration of a graft-versus-leukemia effect suggest that immune-based therapies can be effective in the treatment of childhood leukemia. Efforts to apply new immunotherapy approaches to the treatment of leukemia in pediatrics have recently begun. The optimal reagents, methods, and regimens have yet to be fully defined. Ongoing clinical trials offer promise in that regard.