Here, Sgouros and colleagues provide an overview of the fundamental properties of radiopharmaceutical therapy, discuss agents in use and in clinical development and highlight the associated translational challenges. Introduction Radiopharmaceutical therapy (RPT) is defined by the delivery of radioactive atoms to tumour-associated targets. approach for the treatment of cancer, offering several advantages over existing therapeutic strategies. Here, Sgouros and colleagues provide an overview of the MAPKK1 fundamental properties of radiopharmaceutical therapy, discuss agents in use and in clinical development and highlight the associated translational challenges. Introduction Radiopharmaceutical therapy (RPT) is defined by the delivery of radioactive atoms to tumour-associated targets. RPT is a novel therapeutic modality for the?treatment of cancer, JNJ-5207852 providing several advantages over existing therapeutic approaches. Unlike radiotherapy, the radiation is not administered from outside the body, but instead is delivered systemically or locoregionally, akin to chemotherapy or JNJ-5207852 biologically targeted therapy. The cytotoxic radiation is delivered to cancer cells or to their microenvironment either directly or, more typically, using delivery vehicles that either bind specifically to endogenous targets or accumulate by a wide variety of physiological mechanisms characteristic of neoplasia, enabling a targeted therapeutic approach. Unlike biologic therapy, it is far less dependent on an understanding of signalling pathways and on identifying agents that interrupt the putative cancer phenotype-driving pathway (or pathways). Notably, the clinical trial failure rate of targeted (that is, biologic) cancer therapies is 97% (ref.1), which is in part due to the drugs selected for clinical trial investigation targeting the wrong pathway2. Radionuclides with different emission properties primarily -particles or highly potent -particles are used to deliver radiation. In almost all cases, the radionuclides may be visualized by nuclear medicine imaging techniques to assess targeting of the agent, which provides a substantial advantage over existing therapeutic approaches and enables a precision medicine approach to RPT delivery. Patients with cancer with distant metastases continue to have a grim prognosis despite ongoing efforts with new chemotherapeutics, small-molecule inhibitors, biologics, immune checkpoint inhibitors and various combinations of these; novel therapeutic approaches are therefore vital. Compared with almost all other systemic cancer treatment options, RPT has shown efficacy with minimal JNJ-5207852 toxicity3. In addition, unlike chemotherapy, responses with JNJ-5207852 RPT agents typically do not require many months (or cycles) of therapy and are often observed after a single or at most five injections; side effects such as alopecia or peripheral neuropathy are generally less severe than with chemotherapy, if observed at all. RPT development is a multidisciplinary endeavour, requiring expertise in radiochemistry, radiobiology, oncology, pharmacology, medical physics and radionuclide imaging and dosimetry most pharmaceutical companies are not familiar with the radiation and radionuclide aspects of RPT and the deployment of RPT agents for cancer therapy is also unfamiliar to the oncology community. It is a therapeutic modality that is not consistently identified with any one JNJ-5207852 group of practitioners and it lacks a constituency. For many decades RPT has been a treatment modality of last resort and available only in small clinical trials or as part of compassionate care from a small number of institutions in Europe and even fewer in the USA and the rest of the world. In the sense that RPT has no well-defined community of stakeholders it has been an orphan treatment modality for many years. However, the remarkable potential of RPT directed against primary cancers as well as distant metastases, is now being recognized as an effective, safe and economically and logistically viable treatment modality, receiving renewed attention from both small and large pharmaceutical companies4. The recent approval of -particle-emitting RPT agents that act against neuroendocrine cancers and phaeochromocytomas, the approval of an -emitter RPT for bone metastases of prostate cancer and the highly promising clinical and preclinical preliminary results with RPT agents using other -particle-emitting radionuclides has reignited interest in RPT. This Review provides an overview of the radiochemistry and physics aspects needed to understand the fundamentals of RPT..