Refractory multi-principal-element alloys (RMPEA) are promising alloys for high-temperature (HT) applications if stability, strength, and oxidation resistance in harsh-service conditions can be addressed. The first two HT-strength RMPEAs, MoNbTaW and MoNbTaVW, are equiatomic solid-solutions that have strong mechanical strength at high temperatures, but they are brittle at room temperature. Efforts were made to improve their ductility, but always resulted in a significant loss of HT strength. Fortunately, numerous non-equiatomic RMPEAs do indeed retain single-phase solid solutions (and multiphase for strengthening, controlled by composition) that exhibit superior mechanical properties. By removing the equiatomic constraint, the MPEA composition space expands significantly yet demands an excessive amount of computational and experimental work. The high-throughput (HTP) scheme is one such approach which, when combined with numerically efficient density-functional theory (DFT) methods, can enable accurate MPEA design. Experimentally, methods like rapid alloy prototyping, diffusion-multiples, additive manufacturing, and thin-film-related co-deposition have been successful. Recently, computation materials science has started to play a critical role in HEA development, including high-throughput computational method, machine learning assisted design coupled with modeling/experimental data, and DFT. However, past effort focused on either computation or experiments with a limited synergy of the two. Moreover, there has been limited or no focus on developing numerically efficient ways to directly use DFT in MPEA design. In this work, Gaoyuan Ouyang et al. from the Division of Materials Science and Engineering, Ames Laboratory, developed a numerically efficient screening strategy combining HTP-DFT with experimental validation along with high-fidelity testing for efficiently exploring the vast RMPEA compositional space. In the study, DFT was used to scan composition space using four criteria: (1) formation energy for operational stability: ？150 ≤ Ef ≤ +70meV/atom; (2) higher strength found via interstitial electron density with Young’s moduli E？>？250？GPa; (3) inverse Pugh ratio for ductility: G/B？<？0.57; (4) high melting points: Tm？>？2500？ C. Using rapid bulk alloy synthesis and characterization, the authors found that Mo72.3W12.8Ta10.0Ti2.5Zr2.5 has a good balance of room-temperature and HT mechanical properties. This alloy has comparable high-T compressive strength to well-known MoNbTaW but is more ductile and more creep resistant. It is also superior to a commercial Mo-based refractory alloy and a nickel-based superalloy (Haynes-282) with improved high-T tensile strength and creep resistance.