Background. Thrombosis of synthetic small-diameter bypass grafts remains a major problem. The aim of this article is to review the antithrombotic strategies that have been used in an attempt to reduce graft thrombogenicity. Methods. A PubMed/MEDLINE search was performed using the search terms “vascular graft thrombosis,” “small-diameter graft thrombosis,” “synthetic graft thrombosis” combined with “antithrombotic,” “antiplatelet,” “anticoagulant,” “Dacron,” “PTFE,” and “polyurethane.” Results. The majority of studies on antithrombotic therapies have used either in vitro models or in vivo animal experiments. Many of the therapies used in these settings do show antithrombotic efficacy against synthetic graft materials. There is however, a distinct lack of human in vivo studies to further delineate the performance and limitations of therapies displaying good antithrombotic characteristics. Conclusion. Very few antithrombotic therapies have translated into clinical use. More human in vivo studies are required to assess the efficacy and safety of such therapies.