Anticoagulants are used in several settings to reduce the risk of thromboembolic events, but they can be associated with severe complications, such as potentially fatal bleeding. Two of the most widely used direct oral anticoagulants (DOACs), rivaroxaban and apixaban, are factor Xa inhibitors. If a patient receiving treatment with a factor Xa inhibitor presents with a major bleeding event, the physician must determine whether reversal of anticoagulation is needed. Rivaroxaban and apixaban have relatively short half-lives. In some cases, it may be sufficient to provide supportive care while the agent is metabolized. The administration of a specific agent to reverse factor Xa inhibition may be clinically indicated in certain settings, such as when rivaroxaban and apixaban were given less than 12 hours earlier (assuming normal renal function), when the timing of the previous dose is unknown, or in the event of a catastrophic bleed. The US Food and Drug Administration (FDA) recently granted accelerated approval to andexanet alfa, a recombinant protein analogue of factor Xa, for patients treated with rivaroxaban or apixaban who require reversal of anticoagulation owing to life-threatening or uncontrolled bleeding. Off-label treatments used in this setting include prothrombin complex concentrates.