Along with the globalization of environmental problems and the rapid development of the field of nuclear technologies, the severe irradiation damage of materials has become a big issue, restricting the development of advanced nuclear reactor systems. Refractory high-entropy alloys (RHEAs) have the characteristics of a complex composition, a short-range order, and lattice distortion and possess a high phase stability, outstanding mechanical properties, and excellent irradiation resistance at elevated temperatures; thus, they are expected to be promising candidates for advanced nuclear reactors. This review summarizes the design, preparation, and irradiation resistance of irradiation-tolerant RHEAs. It encompasses a comprehensive analysis of various aspects, including the evolution of defects, changes in microstructure, and the degradation in properties. Furthermore, the challenges and insufficiently researched areas regarding these alloys are identified and discussed. Building on this foundation, the review also provides a forward-looking perspective, outlining potential avenues for future research.