Primary and metastatic malignant bone lesions result in significant pain and disability in oncology patients. Targeted bone-seeking radioisotopes including 153 Samarium ethylene-diamine-tetramethylene-phosphonic acid ( 153 Sm-EDTMP) have been shown to effectively palliate bone pain, often when external beam radiotherapy (EBRT) is not feasible. However, recent evidence also suggests 153 Sm-EDTMP has cytotoxic activity either alone or in combination with chemotherapy or EBRT. 153 Sm-EDTMP may be useful as anti-neoplastic therapy apart from pain palliation in a variety of malignancies. For prostate cancer patients, several phase I and II clinical trials have shown that combined 153 Sm-EDTMP and docetaxel-based chemotherapy can result in >50% decrease in prostate- specific antigen with manageable myelosuppression. In hematologic malignancies, 153 Sm-EDTMP produced clinical responses when combined with bortezomib in multiple myeloma. 153 Sm-EDTMP also can be used with myeloablative chemotherapy for marrow conditioning prior to stem cell transplant. In osteosarcoma, 153 Sm-EDTMP infusion delivers radiation to multiple unresectable lesions simultaneously and provides local cytotoxicity without soft tissue damage that can be combined with chemotherapy or radiation. Prior to routine incorporation of 153 Sm-EDTMP into therapeutic regimens, we must learn how to ensure optimal delivery to tumors, determine which patients are likely to benefit, improve our ability to assess clinical response in bone lesions and further evaluate the efficacy of 153 Sm-EDTMP in combination with chemotherapy, radiation and novel targeted agents.