Cryptogenic stroke (CS) is defined as the presence of cerebral infarcts, the cause which has not been identified despite an appropriate diagnostic evaluation, and it accounts for approximately 30–40% of all ischemic strokes. There is a certain subgroup of CS with embolic characteristics on neuroimaging studies and no evidence of atrial fibrillation alternative or any alternative cause. Recent data suggest that disorders of the atrium, even without atrial fibrillation, could increase thromboembolic risk. The pathological atrial substrate, or atrial cardiopathy (AC), may be an important and underrecognized cause of cryptogenic strokes. This chapter will review the information on the rationale and data behind the concept of atrial cardiopathy, its pathophysiology, proposed biomarkers of atrial cardiopathy, and therapeutic implications.