The term 'embolic stroke of undetermined source' (ESUS) is used to describe patients with a non-lacunar ischaemic stroke without any identified embolic source from the heart or the arteries supplying the ischaemic territory, or any other apparent cause. When the ESUS concept was introduced, covert atrial fibrillation was conceived to be the main underlying cause in the majority of ESUS patients. Another important embolic source in ESUS is the atherosclerotic plaque in the carotid, vertebrobasilar, and intracranial arteries, or the aortic arch-collectively described as supracardiac atherosclerosis. There is emerging evidence showing that the role of supracardiac atherosclerosis is larger than it was initially perceived. Advanced imaging methods are available to identify plaques which high embolic risk. The role of novel antithrombotic strategies in these patients needs to be assessed in randomized controlled trials. This review presents the evidence which points towards a major aetiological association between atherosclerotic plaques and ESUS, summarizes the imaging features which may aid to identify plaques more likely to be associated with ESUS, discusses strategies to reduce the associated stroke risk, and highlights the rationale for future research in this field.