Advanced nuclear energy systems, both fission- and fusion-based, aim to operate at higher temperatures and greater radiation exposure levels than experienced in current light water reactors. Additionally, they are envisioned to operate in coolants such as helium and sodium that allow for higher operating temperatures. Because of these unique environments, different requirements and challenges are presented for both structural materials and fuel cladding. For core and cladding applications in intermediate-temperature reactors (400–650°C), the primary candidates are 9–12Cr ferritic–martensitic steels (where the numbers represent the weight percentage of Cr in the material, i.e., 9–12 wt%) and advanced austenitic steels, adapted to maximize high-temperature strength without compromising lower temperature toughness. For very high temperature reactors (>650°C), strength and oxidation resistance are more critical. In such conditions, high-temperature metals as well as ceramics and ceramic composites are candidates. For all advanced systems operating at high pressures, performance of the pressure boundary materials (i.e., those components responsible for containing the high-pressure liquids or gases that cool the reactor) is critical to reactor safety. For some reactors, pressure vessels are anticipated to be significantly larger and thicker than those used in light water reactors. The properties through the entire thickness of these components, including the effects of radiation damage as a function of damage rate, are important. For all of these advanced systems, optimizing the microstructures of candidate materials will allow for improved radiation and high-temperature performance in nuclear applications, and advanced modeling tools provide a basis for developing optimized microstructures.