Prevention of atrial fibrillation (AF)-related stroke and thromboembolism is an important part of AF management. However, stroke risk varies considerably with associated morbidities and risk factors. Several stroke risk stratification schemes have been developed, and categorize patients' stroke risk into categories based on the presence and combination of risk factors. Based on the perceived level of risk, current guidelines recommend that patients with AF receive some form of antithrombotic therapy. Despite guideline recommendations, however, many patients with AF do not receive adequate thromboprophylaxis. This review will discuss some of the reasons why guidelines are not adhered to in clinical practice and current gaps in knowledge. Low adherence to guidelines is in part related to the drawbacks associated with vitamin K antagonist therapy and to the imperfection of current schemes for stratification of both thromboembolic and bleeding risks. Such drawbacks have highlighted the need for new anticoagulants for the prevention of stroke in patients with AF. The novel oral anticoagulants in development, four of which - dabigatran, rivaroxaban, apixaban and edoxaban - have completed or are completing phase III testing, may overcome some of the limitations of vitamin K antagonist therapy and address the underuse and safety concerns associated with current antithrombotic therapies in patients with AF.