Once the diagnosis of a thrombophilic state has been established, management must include one or more strategies designed to attenuate thrombotic risk and the likelihood of clinical events. In the case of drug-induced arterial thrombosis provoked by oral contraceptives, hormone replacement therapy, heparinoids, cocaine, or thienopyridine-related thrombotic thrombocytopenic purpura (TTP), the offending agent should be discontinued immediately. Anticoagulant therapy and platelet-directed therapies, either alone or in combination, should be considered for patients experiencing a single arterial or venous thrombosis (secondary prevention), with treatment duration determined by diagnostic studies and the persistence of a prothrombotic state. Other specific therapies should be directed at the underlying thrombophilic disorder. These treatments include direct thrombin inhibitors such as argatroban for heparin-induced thrombocytopenia (HIT), myelosuppressive drugs such as hydroxyurea for essential thrombocytosis, plasma exchange for thrombotic thrombocytopenic purpura, and phlebotomy for polycythemia vera. Additionally, the treating physician must seek input early from a hematologist or rheumatologist when managing patients with known or suspected HIT, TTP, and myeloproliferative disorders, or the antiphospholipid syndrome, respectively. This interdisciplinary interface is critical to ensure an optimal outcome when treating patients with arterial thrombophilia.