Positron annihilation spectroscopy (PAS) is widely recognized as a powerful characterization technique in all types of radiation damage studies in nuclear materials. In the past, fission reactor irradiation of reactor pressure vessel (RPV) steels was a primary aim in most studies, while today’s applications of PAS in this field are centered around ion implantation experiments in advanced structural materials. These experiments use hydrogen, helium, heavy ions, and their combination to simulate various radiation environments of future nuclear reactors or nuclear research facilities. The spectrum of ion energies used ranges from a few tens of keV to tens or even hundreds of MeV in proton irradiation or spallation neutron source irradiation experiments. The variety of ion energies, irradiation temperatures, and other experimental conditions poses a major challenge to researchers, who often fail to successfully incorporate the lessons learned from their research. In this paper, we review and supplement recent PAS studies in which structural materials irradiated under a variety of irradiation conditions were investigated using positron annihilation spectroscopy. It summarizes the most important conclusions and lessons learned from the application of PAS in accelerator-based irradiation experiments.