Blood-contacting medical devices are an integral part of modern medicine. Such devices may be used for only a few hours or may be implanted for life. Despite advances in biomaterial science, clotting on medical devices remains a common problem. Systemic administration of antiplatelet drugs or anticoagulants is often needed to reduce the risk of clotting. Although effective, such therapy increases the risk of bleeding, which can be fatal. This chapter (a) describes some of the commonly used blood-contacting devices and their potential complications, (b) provides an overview of the mechanisms that drive device-associated clotting, and (c) reviews the strategies employed to attenuate clotting on blood-contacting medical devices.