Atrial fibrillation (AF) is considered the most common sustained cardiac arrhythmia, and it is associated with a significant risk of adverse events, especially ischemic stroke. Oral anticoagulation is the cornerstone for stroke prevention in AF; for many years, only vitamin K antagonists were used for this purpose, with an absolute risk reduction >60%. However, these agents have limitations, such as narrow therapeutic margins and drug–food and drug–drug interactions. More recently, 4 direct-acting oral anticoagulants (DOACs)—non–vitamin K antagonists—have become available for patients with AF: dabigatran, rivaroxaban, apixaban, and edoxaban. In addition to a comparable efficacy to warfarin in large randomized controlled trials, DOACs were found to promote a lower risk of intracranial bleeding. The strategic dosage and lack of need for periodic prothrombin-time testing make their use attractive, especially for primary or secondary prevention of stroke in older adults. Furthermore, among patients with AF presenting with acute coronary syndrome or undergoing percutaneous coronary intervention, apixaban is associated with a reduction in serious bleeding events when compared with warfarin. On the other hand, there is no evidence of benefit of DOACs in patients with mechanical prosthetic valves or moderate/severe mitral stenosis. Furthermore, the suitability of DOACs in patients with liver disease is still poorly understood, and their safety in patients requiring renal replacement therapy remains uncertain. This review provides an overview of the main trials of DOACs, their pharmacology and safety profile, clinical implications, and best indications in light of the current evidence.