The era in which vitamin K antagonists were the only option for long-term anticoagulation has ended. Patients now have multiple treatment options for prophylaxis for nonvalvular atrial fibrillation and prevention and treatment for venous thromboembolism. Novel oral anticoagulants, consisting of direct thrombin inhibitors and factor Xa inhibitors, are a diverse group of agents that have reduced medication and food interactions compared to warfarin, and they eliminate the need for frequent monitoring. However, patients presenting with novel oral anticoagulant-associated bleeding emergencies represent a diagnostic and therapeutic challenge due to the lack of access to appropriate laboratory testing modalities or well-validated reversal agents. Following the treatment path appropriate for vitamin K antagonists is ineffective and potentially harmful, making novel assays and antidotes necessary. This review examines the evidence on the use and risks of enriched clotting factor preparations as well as the clinical and laboratory evaluation that will guide their management.