Prostate cancer (PC) is the second most common cancer among men, with 1.3 million yearly cases worldwide. Among those cancer-afflicted men, 30% will develop metastases and some will progress into metastatic castration-resistant prostate cancer (mCRPC), which is associated with a poor prognosis and median survival time that ranges from nine to 13 months. Nevertheless, the discovery of prostate specific membrane antigen (PSMA), a marker overexpressed in the majority of prostatic cancerous tissue, revolutionised PC care. Ever since, PSMA-targeted radionuclide therapy has gained remarkable international visibility in translational oncology. Furthermore, on first clinical application, it has shown significant influence on therapeutic management and patient care in metastatic and hormone-refractory prostate cancer, a disease that previously had remained immedicable. In this article, we provide a general overview of the main milestones in the development of ligands for PSMA-targeted radionuclide therapy, ranging from the firstly developed monoclonal antibodies to the current state-of-the-art low molecular weight entities conjugated with various radionuclides, as well as potential future efforts related to PSMA-targeted radionuclide therapy.

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