Systemic radionuclide therapy is gaining popularity in the radiotherapy community and changing the management of painful osseous metastases. This form of therapy has two major advantages: (i) it addresses all sites of involvement; and (ii) selective absorption limits normal tissue dose. As a result, toxicity is reduced and the therapeutic ratio increased. The biokinetics, dosimetry, and clinical experience with these compounds are reviewed. To date, the best studied and most commonly used radionuclide is strontium-89. Large, prospectively randomized clinical trials have demonstrated its efficacy as a first-line therapy or as an adjuvant to external-beam radiotherapy. It is particularly useful when external-beam therapy options have been exhausted, and normal tissue tolerance has been reached. In metastatic prostate cancer, our recent survey suggests the formation of a new paradigm: local field external-beam radiotherapy to the painful index site in combination with prophylactic administration of systemic radionuclides for clinically occult metastases.