Serine　proteases　are　a　large　family　of　enzymes　critical　for　multiple　physiological　processes,　and　proven　diagnostic　and　therapeutic　targets　in　several　clinical　indications.　The　high　similarity　of　active　sites　among　different　serine　proteases　posts　a　challenge　to　reach　high　selectivity　for　inhibitors　of　serine　proteases　targeting　at　the　active　site.　Here,　we　demonstrated　that　one　particular　surface　loop　on　serine　proteases　(autolysis　loop)　can　be　used　to　regulate　their　catalytic　activity,　through　surveying　the　recent　works　including　ours,　and　such　an　approach　can　reach　high　specificity.　The　autolysis　loop　is　highly　variable　among　different　serine　proteases,　explaining　the　high　specificity　of　inhibitors　targeting　the　autolysis　loop.　We　also　outline　the　structural　origin　that　links　the　perturbation　of　the　autolysis　loop　and　the　inhibition　of　protease　activity.　Thus,　the　autolysis　loop　appears　to　be　a　highly　sensitive　allosteric　site　and　can　be　used　as　a　general　handle　to　develop　pharmacological　agents　to　intervene　with　the　activities　of　serine　proteases　in,　eg,　blood　coagulation.