Downscaling catalyst size has long been used to promote the atomic utilization efficiency of catalysts. Single-atom catalysts (SACs) are the current end of this downscaling road, offering the potential of 100% metal atom utilization and excellent catalytic behavior compared with traditional nanoparticle catalysts. However, most development of SACs still relies on trial-and-error experiments because of the insufficient understanding of the distinctive properties of SACs and their structure-activity relationships. This Perspective discusses the path forward toward the rational design of SACs through a summary of understanding regarding the distinctive properties of single-atom active sites, their dynamic changes during the reactions, and the corresponding reaction mechanisms. Major challenges and opportunities for future research on SACs are identified in precisely controlled synthesis, advanced operando characterizations, and discovering the unconventional catalytic mechanisms.