The prognosis of advanced B-large cell lymphoma (B-LCL) in children and adolescents has improved dramatically over the past 25 years (30-40% to 80-90% 5-year event-free survival (EFS)). Using strategies of treatment allocation based upon risk of disease recurrence, the total duration of therapy has been successfully reduced for many patients, and the prior requirement for radiotherapy largely eliminated. Instead of 18-30 months of combined chemotherapy and radiotherapy, current therapy has been decreased to between 6 weeks and 6 months of intensive chemotherapy. Multiagent chemotherapeutic approaches have been optimized with the use of moderate to high-dose methotrexate and further intensification with cytarabine and etoposide. The prognosis for children and adolescents who progress or relapse on current therapy for B-LCL, however, has decreased over the past 25 years with approximately 80% or 90% surviving at the present time. B-LCL in children and adolescents uniformly expresses CD20 and CD22 surface antigens. New treatment strategies employing targeted monoclonal antibody therapy combined with chemotherapy and targeted conjugated monoclonal antibody therapy conjugated with radioactive compounds and toxins are currently being investigated. Future studies utilizing immunophenotyping, cytogenetics, molecular genetics, and gene expression profiles (microarray) are required to better define the biological heterogeneity and differential clinical outcomes among children and adolescents with B-LCL.