Atrial fibrillation (AF) is the most frequent sustained arrhythmia and its prevalence is increasing in developed countries. This progressive increase and the negative impact of this arrhythmia on the patient’s prognosis make AF one of the main healthcare problems faced today. This has led to intense research into the main aspects of AF, one of them being thromboembolism prevention. AF patients have a four to five times higher risk of stroke than the general population. Several factors increase thromboembolic risk in patients with AF and the use of risk scores, such as the Congestive Heart Failure, Hypertension, Age Greater than 75, Diabetes, and Prior Stroke or Transient Ischemic Attack (CHADS2), have been used to identify the best candidates for anticoagulation. Antithrombotic drugs are the mainstay of therapy for embolic prevention. The clinical use of these drugs is based on the risk–benefit ratio, where benefit is the reduction of stroke and systemic embolic events and risk is mostly driven by the increase in bleeding events. Generally, antiplatelets are indicated for low-risk patients in light of the fact anticoagulants are the drug of choice for moderate- or high-risk patients. Vitamin K antagonists have been the only option for oral anticoagulation for the last 50 years. However, these drugs have many pharmacodynamic and pharmacokinetic problems. The problems of anticoagulation with vitamin K antagonists have led to the investigation of new drugs that can be administered orally and have a better dose–response relationship, a shorter half-life and, in particular, higher efficacy and safety without the need for frequent anticoagulation controls. The drugs that have been studied most thoroughly in patients with AF are inhibitors of the activated coagulation factor X and inhibitors of coagulation factor II (thrombin), including ximelagatran and dabigatran. In addition, non-pharmacological therapies have been developed to prevent recurrent embolism in certain patient populations.