The urgent need to combat pollution necessitates a focused reduction in CO2 emissions, positioning nuclear energy as a promising alternative to fossil fuels. The demand for advanced materials in nuclear fission and fusion power plants arises from their challenging operating conditions. While current materials are in use, there is a compelling case for exploring new alternatives that offer improved efficiency, enhanced safety, reduced waste, extended operational lifespans, high-temperature durability, and resistance to high-energy neutron irradiation. High-Entropy Alloys (HEAs) have emerged as a promising solution due to their exceptional properties and untapped compositional possibilities. Their key advantage is sluggish diffusion, which limits the movement of point defects, leading to increased recombination and mitigating hardening and swelling effects. To meet the stringent requirements of reactor environments, HEAs must also exhibit low activation properties. To tackle this challenge, our research focuses on understanding ion-irradiated single-phase HEAs under high-temperature and high-fluence conditions. We aim to uncover the underlying physics of hardening and swelling using a comprehensive suite of experimental and simulation techniques, including TEM, HR-TKD, Astar strain mapping, ACOM, nano-indentation, SIMS, XRD, AFM, micropillar tests, APT, DBS-PALS, DFT, MD, and KMC. The ultimate goal is to develop a robust screening tool with high-throughput capabilities, enabling the efficient evaluation of numerous HEA compositions. This tool will provide a foundation for tailoring HEAs to specific applications. The designed HEAs will not only withstand extreme conditions but also retain balanced mechanical properties, striking an optimal trade-off between hardness and toughness. This progress will pave the way for innovative applications in next-generation nuclear reactors.