Target-specific oral anticoagulants (TSOACs) dabigatran, rivaroxaban and apixaban are approved for the prevention and treatment of thromboembolism in several clinical settings. Bleeding is the major complication of anticoagulant therapy, including TSOACs, and anticoagulant reversal strategies are highly desired for the management of anticoagulant-associated major bleeding in addition to maximum supportive care and procedural/surgical intervention. Unlike VKAs for which vitamin K and coagulation factor replacement with prothrombin complex concentrate (PCC) can restore hemostasis, there are no clinically available agents proven to reverse TSOAC anticoagulant effect and ameliorate TSOAC-related major bleeding. This narrative review critically evaluates the evidence for TSOAC reversal using non-specific reversal agents PCC, activated PCC (APCC) and recombinant activated factor VII (rVIIa) which have been assessed primarily using in vitro experiments, animal models and healthy human volunteers. Aripazine is a novel agent undergoing clinical development for non-specific anticoagulant reversal, including TSOACs. Data are presented regarding specific reversal agents idarucizumab (dabigatran) and andexanet alfa (oral factor Xa inhibitors) currently being evaluated in clinical trials. A practical approach to management of patients with TSOAC-associated bleeding is also provided. There is an urgent need for clinical studies that evaluate the efficacy and safety of reversal strategies for TSOAC-related major bleeding with assessment of clinical outcomes such as bleeding and mortality.