The most common cause of treatment failure in childhood acute lymphoblastic leukemia (ALL) remains relapse, occurring in approximately 15-20% of patients. Survival of relapsed patients can be predicted by site of relapse, length of first complete remission and immunophenotype of relapsed ALL. Bone marrow (BM) and early relapse (< 30 months from diagnosis), as well as T-ALL, are associated with worse prognosis than isolated extramedullary or late relapse (>30 months from diagnosis). Also persistence of minimal residual disease (MRD) at the end of induction or consolidation therapy predicts poor outcome, since children with detectable MRD are more likely to relapse than those in molecular remission, even after allogeneic hematopoietic stem cell transplantation (HSCT). We offer HSCT to any child with high-risk features, since these patients are virtually incurable with chemotherapy alone. By contrast, we treat children with first late BM relapse of B-cell precursor ALL and good clearance of MRD with a chemotherapy approach. We use both systemic and local treatment for extramedullary relapse, mainly represented by radiotherapy and, in case of testicular involvement, by orchiectomy. Innovative approaches, including new agents or strategies of immunotherapy, are under investigation in trials enrolling patients with resistant or more advanced disease.