Atrial fibrillation (AF) is the most common arrhythmia, ranging from 0.1% in patients <55 years to >9% in octogenarian patients. One important issue is represented by the 5-fold increased ischemic stroke risk in AF patients. Hence, the role of anticoagulation is central. Until a few years ago, vitamin K antagonists (VKAs) and low molecular weight heparin represented the only option to prevent thromboembolisms, though with risks. Novel oral anticoagulants (NOACs) have radically changed the management of AF patients, improving both life expectancy and life quality. This review aims to summarize the most recent literature on the use of VKAs and NOACs in AF, in light of the new findings.