Approximately 66,000 Americans develop non-Hodgkin lymphoma (NHL) each year. Although the use of unlabeled antibodies such as rituximab has significantly improved survival when combined with standard chemotherapy regimens, approximately two-thirds of lymphoma patients eventually develop disease recurrence and die of their disease. Novel treatments are urgently needed to cure these patients. One strategy involves the use of radiolabeled immunoconjugates that specifically localize radiation delivery to sites of lymphoma while minimizing toxicity to normal tissues. A growing number of studies support the contention that radiolabeled antibody therapy can improve overall survival of lymphoma patients and lead to durable remissions, with probable cures, in many patients. Various approaches for enhancing the effectiveness of radioimmunoconjugates have been studied, including: use in newly diagnosed lymphoma patients, combination with chemotherapy or other monoclonal antibodies, use with hematopoietic stem cell transplantation, multistep pretargeting strategies to further minimize toxicity, and simultaneous targeting of multiple B-cell antigens. This article summarizes the current knowledge supporting the use of radioimmunotherapy, an underused but effective treatment modality in NHL patients. Cancer 2010;116(4 suppl):1126–33. © 2010 American Cancer Society.