<p>Interstitial alloying has emerged as a powerful strategy to tune microstructure and microproperties of high-entropy alloys (HEAs) due to the strong interaction of interstitials with constituent elements and crystal defects, which enables the development of advanced alloys with superior mechanical and functional properties. The paper reviews the latest progress in the atomic-scale understanding of the effects of various interstitials, including carbon, boron, nitrogen, oxygen, and hydrogen, on the microstructure, stability, mechanical properties, and deformation behavior of HEAs. Emphases are placed on the in-depth insights on the interaction of interstitials with constituent elements and crystal defects, such as vacancies, stacking faults, and grain boundaries. Key parameters for rapid prediction of intrinsic properties of HEAs are also discussed. Finally, we highlight some unsolved issues and provide perspectives for future research directions.</p> Graphical abstract <p></p>