The most common cause of treatment failure in childhood acute lymphoblastic leukemia (ALL) remains relapse, occurring in ~ 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. 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). In addition, persistence of minimal residual disease (MRD) at the end of induction or consolidation therapy predicts poor outcome because children with detectable MRD are more likely to relapse than those in molecular remission, even after allogeneic hematopoietic stem cell transplantation. We offer hematopoietic stem cell transplantation to any child with high-risk features because 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.