Cryptogenic stroke (CS) accounts for 20% to 40% of ischemic strokes. CS is defined as a cortical infarct suggestive of an embolic stroke with no identifiable cardiac etiology, large vessel occlusive disease, or small vessel lacunar stroke. The likely etiologies for CS are patent foramen ovale (PFO) and paroxysmal atrial fibrillation, which can be detected by transesophageal echocardiography and long-term cardiac rhythm monitoring. In a busy academic hospital, the stroke service is frequently asked to provide a rational approach to patients with such a presentation. The 2011 American Heart Association/American Stroke Association recommends that antiplatelet therapy is “reasonable” (Class IIa; Level of Evidence B) for patients with PFO and a clinical presentation of CS. Confounding PFO management is the lack of a controlled trial comparing anticoagulation with antiplatelet therapy in patients with CS, despite the belief that the primary mechanism of PFO-mediated stroke would be that it serves as a conduit for venous emboli. Data from 3 recent prospective PFO closure device trials further compound the management protocols for these patients. Also complicating the management of CS is increasing evidence that paroxysmal atrial fibrillation may be found as often as 30% with extensive monitoring and long-term follow-up of 36 months. Based on these recent developments, we summarize the factors that we deemed relevant in our approach to patients with CS.