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This is an exciting time in hemophilia treatment with the unprecedented development of novel non-factor therapies. These agents have re-balanced hemostasis in patients with hemophilia A and B, with and without inhibitors, tipping the balance toward hemostasis and improved thrombin generation. While there have been numerous publications about the beneficial hemostatic effects and significant bleed reduction possible with these novel non-factor agents, little has been written about the less well-recognized thrombotic complications. Yet, the latter underscores the fine balance between hemostasis and thrombosis and the fact these agents prevent but do not treat bleeds, requiring clotting factor requirement to treat acute bleeds. The purpose of this Commentary is to review thrombotic complications that have occurred with non-factor therapies, risk factors for thrombosis, potential mechanisms, and potential mitigation approaches.