: The concept of high-entropy alloy (HEA) was first proposed in 2004, and the basic principles, based on four core effects, were scientifically confirmed in 2006. The high-entropy effect, severe lattice distortion, sluggish diffusion, and cocktail effect, serve as a strong foundation for the rational design of advanced materials. By exploiting these phenomena, materials selection strategy can be systematic and predictive, and is particularly useful for many applications that demand high performance. While cost remains an important consideration in materials development, performance, reliability, and safety requirements may become the dominant selection criteria in specific applications, such as biomedical implants, aerospace components, and extreme-environment systems, where failure prevention and long-term functionality are critical. With the materials genome approach and the tremendous progress in the fields of chemistry, physics, and quantum mechanics, it is believed that the design of HEAs with unprecedented accuracy. In this paper, systematically how the four core effects can be utilized is explored to tailor the properties of HEAs for innovative and high-performance applications, unlike previous studies that discuss the four core effects independently, this study integrates thermodynamic, geometric, electronic, and kinetic descriptors into a unified multi-parameter framework for application-oriented HEA design.