Serine　proteases　play　critical　roles　in　many　physiological　and　pathological　processes,　and　are　proven　diagnostic　and　therapeutic　targets　in　a　number　of　clinical　indications.　Suppression　of　the　aberrant　proteolytic　activities　of　these　proteases　has　been　clinically　used　for　the　treatments　of　relevant　dis-eases.　Polypeptides　with　10-20　residues　are　of　great　interests　as　medicinal　modulators　of　serine　prote-ases,　because　these　peptides　demonstrate　the　characteristics　of　both　small　molecule　drugs　and　macro-molecular　drugs.　In　this　review,　we　summarized　the　recent　development　of　peptide-based　inhibitors　against　serine　proteases　with　potent　inhibitory　and　high　specificity　comparable　to　monoclonal　antibod-ies.　In　addition,　we　also　discussed　the　strategies　of　enhancing　plasma　half-life　and　bioavailability　of　peptides　in　vivo,　which　is　the　main　hurdle　that　limits　the　clinical　translation　of　peptide-based　drugs.　This　review　advocates　new　avenue　for　the　development　of　effective　serine　protease　inhibitors　and　highlights　the　prospect　of　the　medicinal　use　of　these　inhibitors.　©　2020　Bentham　Science　Publishers.