Inorganic polyphosphate (polyP) is abundant in biological organisms. PolyP is a major component of dense granules of human platelets and is secreted upon platelet activation. Studies from our lab and others have shown that polyP is a potent modulator of the blood clotting cascade, acting as a pro-hemostatic, prothrombotic and proinflammatory agent depending on its polymer size and location. PolyP may represent at least one of the long-sought (patho)physiologic activators of the contact pathway of blood clotting, and its actions may also help to explain previously unexplained abilities of activated platelets to enhance plasma clotting reactions. PolyP may have utility as a hemostatic agent to control bleeding, and conversely, polyP antagonists might have utility as antithrombotic/anti-inflammatory agents with reduced bleeding side effects. The detailed molecular mechanisms by which polyP modulates blood clotting reactions still remain to be elucidated.