Cryptogenic stroke comprises about one-quarter of ischemic strokes with high recurrence rate; however, studies specifically investigating the features and treatment of this stroke subtype are rare. The concept of ’embolic stroke of undetermined source’ (ESUS) may facilitate the development of a standardized approach to diagnose cryptogenic stroke and improve clinical trials. Since recent large randomized control trials failed to demonstrate a reduction in stroke recurrence with anticoagulants, anti-platelet agents remain the first-line treatment for ESUS patients. Nevertheless, patients with high risk of stroke recurrence (e.g., those with repeated embolic infarcts despite aspirin treatment) require a more extensive survey of stroke etiology, including cardiac imaging and prolonged cardiac rhythm monitoring. Anticoagulant treatments may still benefit some subgroups of high-risk ESUS patients, such as those with multiple infarcts at different arterial territories without aortic atheroma, the elderly, or patients with high CHAD-VASc or HOVAC scores, atrial cardiopathy or patent foramen ovale. Several important ESUS clinical trials are ongoing, and the results are anticipated. With rapid progress in our understanding of ESUS pathophysiology, new subcategorizations of ESUS and assignment of optimal treatments for each ESUS subgroup are expected in the near future.Copyright © 2020. Published by Elsevier B.V.