Due to the elusive structure-function relationship, traditional nanocatalysts always yield limited catalytic activity and selectivity, making them practically difficult to replace natural enzymes in wide industrial and biomedical applications. Accordingly, single-atom catalysts (SACs), defined as catalysts containing atomically dispersed active sites on a support material, strikingly show the highest atomic utilization and drastically boosted catalytic performances to functionally mimic or even outperform natural enzymes. The molecular characteristics of SACs (e.g., unique metal-support interactions and precisely located metal sites), especially single-atom iron catalysts (Fe-SACs) that have a similar catalytic structure to the catalytically active center of metalloprotease, enable the accurate identification of active centers in catalytic reactions, which afford ample opportunity for unraveling the structure-function relationship of Fe-SACs. In this review, we present an overview of the recent advances of support materials for anchoring an atomic dispersion of Fe. Subsequently, we highlight the structural designability of support materials as two sides of the same coin. Moreover, the applications described herein illustrate the utility of Fe-SACs in a broad scope of industrially and biologically important reactions. Finally, we present an outlook of the major challenges and opportunities remaining for the successful combination of single Fe atoms and catalysts.