A series of immunological and physiological barriers must be overcome for the successful clinical application of xenotransplantation. The acute phases of xenograft rejection have been prevented or at least attenuated by a variety of interventions including treatment of the recipient and genetic modification of the donor. However, recent data suggest that xenografts have a heightened susceptibility to intravascular thrombosis, a process that is emerging as a major contributor to xenograft loss. Current data strongly suggest that thrombosis is primarily a direct consequence of the rejection process, but it may also be facilitated by the failure of porcine regulators of coagulation to efficiently regulate the primate coagulation cascade. Systemic anticoagulant therapy has met with limited success and poses significant risks. Genetic strategies to express antithrombotic agents on xenograft endothelium appear to be more promising and achievable, with candidate molecules including human and leech anticoagulants and the antiplatelet enzyme CD39. Deletion of porcine procoagulants may also prove to be a useful approach.