Platelets play an essential role in the regulation of hemostasis and thrombosis and controlling their level of activation is central to prevention of occlusive clot formation and stroke. Although a number of anti-platelet targets have been identified to address this issue including COX-1, the P2Y(12) receptor, the integrin αIIbβ3, and more recently the protease-activated receptor-1, these targets often result in a significant increased risk of bleeding which may lead to pathologies as serious as the thrombosis they were meant to treat including intracranial hemorrhage and gastrointestinal bleeding. Therefore, alternative approaches to treat uncontrolled platelet activation are warranted. Platelet-type 12-lipoxygenase is an enzyme which oxidizes the free fatty acid in the platelet resulting in the production of the stable metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). The role of 12-HETE in the platelet has been controversial with reports associating its function as being both anti- and pro-thrombotic. In this review, the role of 12-lipoxygenase and its bioactive metabolites in regulation of platelet reactivity, clot formation, and hemostasis is described. Understanding the mechanisms by which 12-lipoxygenase and its metabolites modulate platelet function may lead to the development of a novel class of anti-platelet therapies targeting the enzyme in order to attenuate injury-induced clot formation, vessel occlusion and pathophysiological shifts in hemostasis.