Matriptase　is　a　type　II　transmembrane　serine　protease,　which　has　been　suggested　to　play　critical　roles　in　numerous　pathways　of　biological　developments.　Matriptase　is　the　activator　of　several　oncogenic　proteins,　including　urokinase-type　plasminogen　activator　(uPA),　hepatocyte　growth　factor　(HGF)　and　protease-activated　receptor　2　(PAR-2).　The　activations　of　these　matriptase　substrates　subsequently　lead　to　the　generation　of　plasmin,　matrix　metalloproteases　(MMPs),　and　the　triggers　for　many　other　signaling　pathways　related　to　cancer　proliferation　and　metastasis.　Accordingly,　matriptase　is　considered　an　emerging　target　for　the　treatments　of　cancer.　Thus　far,　inhibitors　of　matriptase　have　been　developed　as　potential　anti-cancer　agents,　which　include　small-molecule　inhibitors,　peptide-based　inhibitors,　and　monoclonal　antibodies.　This　review　covers　established　literature　to　summarize　the　chemical　and　biochemical　aspects,　especially　the　inhibitory　mechanisms　and　structure-activity　relationships　(SARs)　of　matriptase　inhibitors　with　the　goal　of　proposing　the　strategies　for　their　future　developments　in　anti-cancer　therapy.