Antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome is a difficult challenge because of the need of taking into consideration three different issues: the cardiac ischemic risk related to coronary artery disease and its treatment with angioplasty and stenting; the thromboembolic risk associated with atrial fibrillation; and the hemorrhagic risk related to the combined use of antiplatelet therapy (with one or two agents) and oral anticoagulant therapy.Data from many trials and meta-analyses currently support a combination therapy with oral anticoagulants (vitamin K antagonists or direct oral anticoagulants) and antiplatelet agents (aspirin and clopidogrel in dual or single antiplatelet therapy).Recently completed and ongoing trials aim to tackle the still controversial issues of this therapy: the choice of the anticoagulant agent and its dosage; the choice of the antiplatelet agent; the use of single or dual antiplatelet therapy and its duration.