Target-specific oral anticoagulants are now available for the prevention of stroke in patients with atrial fibrillation. These medications have many advantages, including fixed dosing, predictable anticoagulation without the need for monitoring, and few food or drug interactions. On the down side, their anticoagulant effects cannot be readily measured in clinical practice, and there are no known antidotes to reverse their anticoagulant effects. Clinical trials have shown superiority or noninferiority of these anticoagulants when compared with warfarin for reduction in incidence of stroke or systemic embolism, major bleeding, and mortality rates. Based on these findings, recent guidelines have supported the use of dabigatran compared with warfarin (other agents were not included in the guideline). Yet, there are concerns that these new agents may not be appropriate for all patients. Patients who are on warfarin and have stable and therapeutic anticoagulation may see no improvement in outcomes if changed to one of the new anticoagulants. Patients with decreased renal function may be at increased risk for bleeding if deterioration in renal function occurs. Management of bleeding events is complicated by the inability to reverse the new medications' anticoagulant effects. Medication noncompliance may result in more adverse outcomes due to the short half-life of these agents compared with warfarin. Prescribers need to be aware of these limitations as these medications are incorporated into clinical practice. Patients and clinicians need to understand the risk and benefits, and patients need to be engaged with their health care providers in decision making.