Embolic stroke of undetermined source (ESUS) is a new clinical entity which requires an accurate diagnostic work-up. The involvement of the cardiologist in this challenge is of paramount importance as in many cases an occult cardioembolic source is detectable. In the absence of subclinical atrial fibrillation detectable by prolonged ECG monitoring, potential causes of ESUS include atrial cardiomyopathy, left ventricular dysfunction or heart failure, aortic plaques and patent foramen ovale. The assessment of a causal relationship between these cardiac abnormalities and ESUS is often a difficult challenge and the randomized clinical trials performed so far failed to demonstrate a superiority of direct oral anticoagulants (DOAC) over aspirin. In selected individual patients with heart failure in sinus rhythm with high CHA2DS2-VASc score, or aortic plaques with thrombotic component, oral anticoagulation with DOAC might be considered even in the absence of evidence from randomized clinical trials.