Single-atom heterogeneous catalysts (SAHCs) provide an enticing platform for understanding catalyst structure-property-performance relationships. The 100% atom utilization and adjustable local coordination configurations make it easy to probe reaction mechanisms at the atomic level. However, the progressive deactivation of metal-single-atom (MSA) with high surface energy leads to frequent limitations on their commercial viability. In this review, we focus on the atomistic-sensitive reactivity and atomistic-progressive deactivation of MSA to provide a unifying framework for specific functionality and potential deactivation drivers of MSA, thereby bridging function, purpose-modification structure-performance insights with the atomistic-progressive deactivation for sustainable structure-property-performance accessibility. We first systematically explore the dominant functionalization of atomically precise MSA acting on properties and reactivity encompassing precise photocatalytic reactions. Afterwards, a detailed analysis of various deactivation modes of MSA and strategies to enhance their durability are presented, providing valuable insights into the design of SAHCs with deactivation-resistant stability. Finally, we complete with a look into the remaining challenges and future perspectives of SAHCs towards industrialization, anticipating shedding some light on the next stage of atom-economic chemical/energy transformations. This article is protected by copyright. All rights reserved.