The median survival for patients with advanced indolent non-Hodgkin's lymphoma (NHL) has remained at 7 to 8 years since the 1960s. Targeted treatment using radioimmunotherapy (RIT), radiolabeled monoclonal antibodies directed against tumor-specific antigens, is an attractive option for this patient population, combining the advantages of an active biologic therapy with low dose-rate irradiation of an inherently radiosensitive tumor. Two anti-CD20 RIT agents have now been approved for the treatment of refractory NHL: 90Y-ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, San Diego, CA, and Schering AG, Berlin, Germany) is approved in both the United States and Europe, and 131I-tositumomab (Bexxar; Corixa Corp, Seattle, WA) is approved only in the United States. This article discusses the development of 131I-tositumomab. Because 131I-labeled antibody clearance varies significantly among patients, prescription of 131I-tositumomab activity must be based on a calculated total-body dose derived from quantitative whole-body imaging. The maximum tolerated total-body dose has been established at 75 cGy in patients with adequate bone marrow reserves and less than 25% bone marrow involvement by lymphoma (65 cGy in patients with mild thrombocytopenia; 45 cGy in patients who have received stem cell transplantation). In a phase III trial, overall response rate (ORR) and complete response (CR) rate were significantly higher following 131I-tositumomab than following the patient's last qualifying chemotherapy (ORR, 65% v 28%; P <.001; CR, 20% v 3%; P <.001). 131I-tositumomab has also been shown to be effective in patients who are refractory to rituximab (ORR, 70%; CR, 32%) and as first-line therapy in patients with NHL (ORR, 97%; CR, 63%). The major side effects of 131I-tositumomab are hematologic. In the phase III study, 20% of patients experienced grade 4 neutropenia and 22% experienced grade 4 thrombocytopenia. Myelodysplastic syndromes or secondary acute myeloid leukemia have been reported in 8.4% of patients with chemotherapy-refractory disease treated with 131I-tositumomab, but have not been observed to date in patients receiving 131I-tositumomab as first-line therapy. Future progress in NHL management is likely to include RIT as part of a multi-modality approach; trials are planned or currently underway to investigate the combination of RIT with chemotherapy regimens.