Bone marrow recurrence of adult acute lymphoblastic leukemia is typically an aggressive and most often rapidly fatal condition, an ideal setting for testing the latest research developments and experimental therapeutic options. Here we review recurrence mechanisms and treatment possibilities in order to identify the most appropriate clinical conduct. Choice of retreatment drugs and their dosages, related or unrelated donor bone marrow transplants, autologous peripheral blood stem cell transplants, immune manipulations, reversal of drug resistance, and restoration of apoptosis are all part of an integrated short-term therapeutic and decisional network to be developed for specific patient and disease prognostic subgroups.