Prostate cancer is the most diagnosed malignancy in men in the United States and the second leading cause of cancer-related death. For localized disease, radiation therapy is a standard treatment that is often curative. For metastatic disease, radiation therapy has been primarily used for palliation, however, several newer systemic radiation therapies have been demonstrated to significantly improve patient outcomes and improve survival. In particular, several targeted radionuclide therapies have been approved for the treatment of advanced-stage cancer, including strontium-89, samarium-153, and radium-223 for bone-metastatic disease, and lutetium-177-labeled PSMA-617 for patients with prostate-specific membrane antigen (PSMA)-expressing metastatic castration-resistant prostate cancer (mCRPC). Contrarily, immune-based treatments have generally demonstrated little activity in advanced prostate cancer, with the exception of the autologous cellular vaccine, sipuleucel-T. This has been attributed to the presence of an immune-suppressive prostate cancer microenvironment. The ability of radiation therapy to not only eradicate tumor cells but also potentially other immune-regulatory cells within the tumor immune microenvironment suggests that targeted radionuclide therapies may be well poised to combine with immune-targeted therapies to eliminate prostate cancer metastases more effectively. This review provides an overview of the recent advances of targeted radiation agents currently approved for prostate cancer, and those being investigated in combination with immunotherapy, and discusses the challenges as well as the opportunities in this field.