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　diseases.　Polypeptides　with　10-20　residues　are　of　great　interests　as　medicinal　modulators　of　serine　proteases,　because　these　peptides　demonstrate　the　characteristics　of　both　small　molecule　drugs　and　macromolecular　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　antibodies.　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.