Systemically administered, beta-emitting radionuclides provide effective pain relief for many patients with symptomatic osseous metastases. Unfortunately, substantial numbers of patients achieve incomplete pain resolution, and some patients obtain no pain relief at all. In addition, there is little evidence that therapy with these radioisotopes results in improved overall survival, and relatively few patients exhibit evidence of significant antitumor activity. Strategies must be developed to enhance the effectiveness of this form of therapy. The possibilities of improved efficacy through the use of increased radionuclide dose, as well as radionuclide therapy in combination with colony-stimulating factors, radiosensitizing chemotherapy, bisphosphonates, and wide-field irradiation, will be explored, and the current literature as well as future plans will be reviewed. Many of these strategies hold promise for enhancing the palliative and anticancer effects of this form of therapy.