Protease　inhibitors　are　of　considerable　interest　as　anticancer　agents.　Matrix　metalloproteinases　(MMPs)　were　the　earliest　type　of　proteases　considered　as　anticancer　targets.　The　developments　of　MMP　inhibitors　(MMPIs)　by　pharmaceutical　companies　can　be　dated　from　the　early　1980s.　Thus　far,　none　of　the　over　50　MMPIs　entering　clinical　trials　have　been　approved.　This　work　summarizes　the　reported　studies　on　the　structure　of　MMPs　and　complexes　with　ligands　and　inhibitors,　based　on　which,　the　authors　analyzed　the　clinical　failures　of　MMPIs　in　a　structural　biological　manner.　Furthermore,　MMPs　were　systematically　compared　with　urokinase,　a　protease-generating　plasmin,　which　plays　similar　pathological　roles　in　cancer　development;　the　reasons　for　the　clinical　successes　of　urokinase　inhibitors　and　the　clinical　failures　of　MMPIs　are　discussed.