Urokinase-type　plasminogen　activator　(uPA)　is　one　of　the　two　physiological　serine　proteases　responsible　for　the　activation　of　plasminongen　to　plasmin.　uPA　activity　is　regulated　by　its　inhibitors　(PAI-1　and　PAI-2)　and　its　receptor　(uPAR),　and　an　expanding　list　of　their　interacting　proteins.　In　addition　to　plasminogen　activation,　this　system　also　plays　important　roles　in　the　regulation　of　many　cellular　processes　including　cell　proliferation,　adhesion　and　migration.　It　is　beyond　reasonable　doubt　that　this　enzyme　system　plays　a　central　role　in　tumor　biology　and　represents　a　high　potential　target　for　therapeutic　intervention　of　tumor　growth　and　metastasis.　During　the　past　fifteen　years,　crystal　structures　of　uPA　and　its　inhibitors　have　facilitated　the　development　of　uPA　inhibitors.　Many　crystal　structures　of　proteins　in　the　uPA/uPAR　system　have　also　been　reported　recently,　especially　a　series　of　structures　of　uPAR　and　its　complexes　with　vitronectin　and　uPA,　facilitating　the　development　and　evaluation　of　uPAR　inhibitors.　Recent　progress　on　uPA　inhibitors　will　be　summarized　in　this　article.　The　unique　structural　features　and　the　druggable　potentials　of　these　new　structures　will　also　be　discussed.　©　2011　Bentham　Science　Publishers.