The incidence and prevalence of atrial fibrillation (AF) is expected to more than double between 2010 and 2030. Accordingly, the use of non-vitamin K oral anticoagulant (NOAC) agents for thromboembolic stroke prevention is anticipated to increase. The development of effective and safe antidotes is needed to address the unmet need for rapid anticoagulation reversal. The immediate role for these novel antidotes is for reversal of NOAC activity in life threatening bleeding and urgent surgical intervention. In addition, reversal agents may play an important role in simplifying bridging protocols in the peri-procedural period for catheter ablation of AF and elective surgery. Currently, novel reversal agents are either decoy drug receptors or small molecule non-specific anticoagulant activity inhibitors. These agents are at various stages of FDA investigation and approval, with emerging prospective data for safety and efficacy. The purpose of this review is to outline the currently developed NOAC molecular antagonists, their potential clinical roles and future directions.