The high temperature and irradiation response of a new class of nanostructured ferritic alloys have been investigated by atom probe tomography. These materials are candidate materials for use in the extreme environments that will be present in the next generation of power generating systems. Atom probe tomography has revealed that the yttria powder is forced into solid solution during the mechanical alloying process andsubsequently 2-nm-diameter Ti-, Y- and O-enriched nanoclusters are formedduring the extrusion process. These nanoclusters have been shown to be remarkably stable during isothermal annealing treatments up to 0.92 of the melting temperature and during proton irradiation up to 3 displacements per atom. No significant difference in sizes, compositions and number densities of the nanoclusters was also observed between the unirradiated and proton irradiated conditions. The grain boundaries were found to have high number densities of nanoclusters as well as chromium and tungsten segregation which pin the grain boundary to minimize creep and grain growth.