The introduction in the therapeutic armamentarium of three new oral anticoagulants for the prevention of thromboembolism in atrial fibrillation (AF) has stimulated the development of this position paper from the Italian Association of Hospital Cardiologists (ANMCO). First, the pathophysiology of arterial thromboembolism in AF is reviewed, describing the mechanisms of action of the new oral anticoagulants, their pharmacology and pharmacokinetics, and highlighting differences and similarities observed in preclinical studies and trials. Stratification of thromboembolic and bleeding risk is made using different risk scores; a comprehensive analysis of the various international guidelines should emphasize convergences or divergences. An in-depth examination of the limitations of current therapeutic strategies for the prevention of stroke in non-valvular AF provides insight into the difficulty in maintaining adequate adherence to therapy with warfarin and a constant and effective anticoagulation, without wide fluctuations in prothrombin time international normalized ratio (INR) values. Clinical trials of new oral anticoagulants for AF are discussed in detail in the present document, with a focus on similarities and differences, efficacy and safety data, and the net clinical benefit of each new oral anticoagulant. Results obtained in elderly patients, or in patients with renal, liver and ischemic heart disease or previous stroke are reported separately, as well as those regarding combination therapy with antiplatelet agents. Finally, this document provides indications, practical applications and cost-effectiveness analysis of each new oral anticoagulant. It is of utmost importance to know how treatment should be started, how you should switch from warfarin, which patients should be maintained on warfarin, how and when cardioversion, catheter ablation or appendage closure should be performed, what drug and food interactions may affect these medications, and how treatment adherence may be improved to avoid therapy discontinuation. An accurate examination of the risk of bleeding is also provided, with special reference to laboratory monitoring of renal and hepatic function, timing for discontinuing these medications prior to surgery, and treatment of patients with major and minor bleeding.