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Two classes of materials which show great promise as next-generation, high-temperature engineering alloys are nanocrystalline metals and refractory high entropy alloys (RHEAs) as they have been shown to exhibit desirable high-temperature properties. Processing-structure-property relationships are often not well-understood in these materials however, as characterization of their microstructural features can be exceedingly difficult. Herein, aberration-corrected scanning transmission electron microscopy was applied to characterize two model alloys on the atomic scale to further elucidate their structure-property relationships and evaluate mechanisms responsible for their enhanced thermo-mechanical behavior.The primary objectives in this work were to investigate the effects of LiH doping on nanoscale particle formation and stability in nanocrystalline Cu-3at.%Ta and to determine whether LiH doping is an effective strategy to further enhance the alloy�s thermo-mechanical behavior. LiH doping was determined to have a profound effect on the thermo-mechanical stability of nanocrystalline Cu-3Ta. An optimal dopant concentration of 0.5 at.% was determined to induce a morphological change to nanoscale particles. Faceted particles in the optimally doped alloy exhibited enhanced coherency and stability, as compared to those observed in binary Cu-3Ta, and were determined to be the primary reason for the alloy�s enhanced thermo-mechanical stability. Based upon this work, copper-based alloys can now be considered strong candidates for high-temperature applications. Another two primary objectives in this study were to explore the effect of various processing conditions on contamination of nanocrystalline MoNbTaW, and its effect on the alloy�s thermo-mechanical behavior and strengthening mechanisms. Several impurities, originating from the use of various milling media and cryogens, were determined to have a significant impact on the thermo-mechanical behavior of MoNbTaW. Non-metallic impurities, such as C and N, played an influential role in destabilizing the alloy�s single-phase solid-solution microstructure. Several complex ceramic phases were identified and determined to contribute to variations in hardness, as large as 5GPa. Several thermal stability and strengthening mechanisms were identified and evaluated. Pore drag was determined to be the most dominant stability mechanism, while Hall-Petch strengthening and secondary phases were determined to be the most dominant strengthening mechanisms. These results provide a detailed understanding of the processing-structure-property relationships in mechanically alloyed MoNbTaW. In either experiment, design criteria have been highlighted which will guide the future design of nanocrystalline metals and RHEAs with enhanced stability and hardness.