Simple SummaryDespite the use of surgery and treatments that inhibit the androgen axis signaling, prostate cancer patients invariably become resistant to castration. In the case of metastatic disease, several alternatives have emerged in the past decade with the development of radionuclide therapies. These treatments may represent an interesting option as they could target either the microenvironment of sclerotic bone metastases or proteins that are specifically expressed at the surface of cancer cells, as it is the case with the prostate-specific membrane antigen. This review summarizes the clinical trials evaluating the efficacy of radionuclide therapies in patients with locally advanced or metastatic prostate tumors. Besides the theragnostic use of radionuclides, it also discusses the recent encouraging results that were obtained with177Lu-PSMA-617 and the specific requirements for the use of this class of medication.AbstractProstate cancer represents the second cause of death by cancer in males in western countries. While early-stage diseases are accessible to surgery and/or external radiotherapy, advanced metastatic prostate cancers are primarily treated with androgen deprivation therapy, to which new generation androgen receptor antagonists or taxane-based chemotherapies are added in the case of tumor relapse. Nevertheless, patients become invariably resistant to castration with a median survival that rarely exceeds 3 years. This fostered the search for alternative strategies, independent of the androgen receptor signaling pathway. In this line, radionuclide therapies may represent an interesting option as they could target either the microenvironment of sclerotic bone metastases with the use of radiopharmaceuticals containing samarium-153, strontium-89 or radium-223 or tumor cells expressing the prostate-specific membrane antigen (PSMA), a protein found at the surface of prostate cancer cells. This review gives highlights the chemical properties of radioligands targeting prostate cancer cells and recapitulates the clinical trials evaluating the efficacy of radionuclide therapies, alone or in combination with other approved treatments, in patients with castration-resistant prostate tumors. It discusses some of the encouraging results obtained, especially the benefit on overall survival that was reported with [177Lu]-PSMA-617. It also addresses the specific requirements for the use of this particular class of drugs, both in terms of medical staff coordination and adapted infrastructures for efficient radioprotection.