For over two decades, valuable insights have been accumulated from epidemiologic studies and randomized trials about the risks for and prevention of AF-related stroke. AF substantially raises the risk of stroke, most likely through an atrio-embolic mechanism. Warfarin and other members of its class of oral anticoagulants targeted at an INR of 2.5 can abrogate the risk of stroke attributable to AF effectively and fairly safely. High-quality management of anticoagulation can be achieved in usual clinical care. These insights have important implications for the care of individual patients and more generally for public health. Future research is needed to specify the risk of stroke and hemorrhage among patients with AF better, particularly among older individuals, to optimize use of antithrombotic agents, and to define the role of recently developed antithrombotic drugs and invasive nondrug approaches.