Hyperacute rejection of vascularized discordant xenografts is induced by natural antibodies and mediated by complement and associated coagulation factor activation. This immediate rejection process can now be effectively managed by complement inhibition. However, acute vascular rejection or delayed xenograft rejection then ensues and can result in destruction of the organ within days to weeks. This form of rejection is associated with vascular inflammation, thrombocytopenia, and the consumption of coagulation factors. Primary biologic incompatibilities of the xenograft with respect to regulation of clotting could further amplify this process. Additionally, infection of the xenograft vascular endothelium by cytomegalovirus or other pathogens may cause severe vascular injury. Interventions with standard and novel anticoagulant/antithrombotic therapies in a systemic or targeted manner should have beneficial effects with respect to prolongation of xenograft survival. This article focuses on the progress that has been made toward the understanding of the coagulation disturbances accompanying xenotransplantation.