Bone pain associated with advanced prostate and other cancers is a frequent and significant complication, and the effective management of metastatic bone disease and accompanying symptoms continues to be one of the major problems facing patients and their physicians. Treatment is in part dependent on prior treatments; usually a combination of systemic and local modalities is used because no single treatment regimen is effective for an extended period of time. The 3 radionuclides currently approved for treatment of bone pain (phosphorus-32, strontium-89, and samarium-153) are discussed in this review as viable treatment options, with emphasis on the third-generation agent in this category, samarium Sm 153 lexidronam. Clinical trial data are described that support the use of this agent in patients with hormone-refractory prostate cancer with painful metastatic bone disease, and the efficacy of and role for combination therapies are also discussed.