Abstract: Background: Embolic stroke of undetermined source (ESUS), a subtype of cryptogenic stroke, was defined as acute ischemic stroke displaying an embolic or non-lacunar brain infarct pattern on imaging without significant extra or intracranial ipsilateral vessel stenosis or without an identifiable cardioembolic source such as atrial fibrillation (AF) or left ventricular thrombi (Hart et al., 2014). ESUS patients tend to be younger than other stroke patients and have a lower incidence of traditional risk factors such as hypertension, diabetes and hypercholesterolemia, that are key contributors for the development of atherosclerosis, the substrate for small and large vessel disease. Two large clinical trials of embolic stroke of unknown source comparing the direct acting oral anticoagulants rivaroxaban and dabigatran to antiplatelet therapy for secondary stroke prevention, the New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus aspirin to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) (Hart et al., 2018) and Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source (RESPECT-ESUS) (Diener et al., 2019), showed not only no benefit for ESUS patients treated with oral anticoagulation to prevent recurrent strokes, but showed even higher risk of bleeding while treated with rivaroxaban. Consequently, the study hypothesis of prevention of recurrent stroke by oral anticoagulation with dabigatran and rivaroxaban in patients diagnosed with ESUS had to be rejected, keeping aspirin as primary secondary prevention treatment for this stroke subtype. Although the reasons for the negative study results are probably multifactorial, posthoc analysis and recent cardiac monitoring studies in ESUS patients suggested that AF may not account for the majority of stroke events in ESUS patients (for example see expert review on ESUS concept, etiology and diagnostic: Schäbitz et al., 2020). In addition to aspects of diagnosis and etiology of ESUS, this topical review will discuss recent evidence from prespecified subgroups of the NAVIGATE- and RESPECT-ESUS trials suggesting a benefit for patients treated with oral anticoagulation with regard to secondary stroke prevention.