Single-atom　catalysts　have　become　the　forefront　and　hotspot　in　catalysis　research　due　to　their　unique　structural　characteristics　such　as　extreme　atomic　utilization　efficiency　and　uniformity　of　reaction　centers.　To　break　through　the　bottleneck　on　their　intrinsic　activity　enhancement,　arduous　efforts　have　been　made　to　regulate　the　metal　single-atomic　sites.　Herein,　with　a　special　interest　in　interatomic　interfaces　and　interactions,　our　review　focuses　on　the　atomic-level　regulation　strategies　of　single-atom　catalysts,　including　nonmetal　heteroatom　doping　and　polymetallic　active　site　construction,　referring　to　the　introduction　of　nonmetal　or　metal　atoms,　respectively,　into　primitive　metal　single-atomic　sites.　We　summarize　the　progress　of　these　two　strategies　in　optimizing　single-atom　active　sites　from　the　perspectives　of　synthesis,　application,　and　mechanism.　We　start　from　a　systematic　overview　of　the　atomic-level　regulation　methods　and　corresponding　fabrication　routes,　followed　by　a　comprehensive　summary　of　the　current　advances　in　some　typical　electrocatalytic　reactions.　Then　we　expound　on　the　synergistic　reaction　mechanism　and　the　intrinsic　structure-activity　relationship　after　regulation.　In　the　final　part,　we　discuss　the　challenges　and　opportunities　of　these　two　atomic-level　regulation　strategies　for　further　development.　Our　review　of　the　atomic-level　regulation　of　single-atom　catalysts　gives　significant　insight　into　the　rational　design　of　atom-efficient　catalysts　and　adds　depth　and　breadth　to　the　fundamental　understanding　of　atomically　precise　catalysis　by　elucidating　its　intrinsic　mechanisms.