Bone-targeted radiopharmaceuticals have an established role as safe and effective agents for the treatment of men with bone-metastatic castration-resistant prostate cancer (CRPC). Three FDA approved radiopharmaceuticals are available for use by clinicians including 153samarium-EDTMP, 89strontium chloride, and 32phosphorus. Data from placebo-controlled randomized trials support the palliative use of these compounds but no consensus currently exists regarding how these compounds should be sequenced with other agents known to be active in the CRPC patient. Multiple factors, including market forces, have limited current use. Newer bone-targeted isotopic therapies are currently under development and large phase III multinational placebo-controlled trials in bone-metastatic CRPC patients are currently being planned for 223radium. Combinations of radiopharmaceuticals and chemotherapy have yielded promising survival results in small randomized studies, but confirmation of survival benefit in larger studies has yet to occur. Various combinations of radiopharmaceuticals and chemotherapy are currently under active investigation.