Among all pediatric cancers, acute lymphoblastic leukemia (ALL) is the most common malignant disease in childhood and adolescence. Over the past decades, substantial achievements have been made resulting in successful treatment of pediatric ALL and cure rates of more than 80%. Despite this success in pediatric oncology, therapy fails in about 20% of the patients leading to reoccurrence of the disease associated with clearly reduced prognosis and outcome. However, the majority of patients encountering relapse are not identified using the currently available risk markers and extramedullary leukemia manifestation outside the hematopoietic system as for example in the central nervous system remains a diagnostic and therapeutic challenge. Moreover, although generally well tolerated, anti-leukemia therapies bear the risk of late sequelae and side effects, in particular for intensified treatment in relapse situations. These problems and limitations clearly highlight the need for less toxic treatment modalities including directed therapies acting on identified targets and improved risk stratification.