Atrial fibrillation (AF) is the most common cause for thromboembolic stroke. Oral anticoagulation with warfarin is still the most effective therapy in patients with AF, who are at an increased risk for stroke. Nevertheless, warfarin therapy has several limitations; therefore, new anticoagulants like warfarin analogs, thrombin inhibitors, or factor Xa inhibitors have been developed. Some of them are currently being tested in phase III trials in patients with AF. Furthermore, the pathophysiology of prothrombotic endocardial remodeling in fibrillating atria suggests that angiotensin II increases prothrombotic expression of vascular adhesion molecules at the atrial endocardium. Thus, novel anticoagulants or hybrid therapy with a combination of anticoagulants with inhibitors of endocardial remodelling like angiotensin II receptor blockers appear to be attractive future perspective approaches.