According to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification, embolic stroke of undetermined source (ESUS) has refined the old definition of cryptogenic stroke. More sophisticated criteria and a well-defined diagnostic workup point out the embolic nature of this disease. Because ESUS is associated with a high stroke recurrence, a clear risk prediction and management is of utmost importance to improve prognosis. To date, standard pharmacotherapy consists of antiplatelet drugs and statins. This review attempts to provide an overview on the diagnostic criteria, prognosis, and current clinical trials evaluating the value of direct oral anticoagulants for secondary prevention after ESUS.