Oral anticoagulation (OAC) is the established therapy to prevent ischemic stroke in high-risk patients with atrial fibrillation (AF) and it reduces the threat of recurrence in those who had a cardioembolic stroke. However, OAC is associated with a substantial risk of major bleeding. Therefore, device-based occlusion therapies including left atrial appendage occlusion (LAAO) and patent foramen ovale (PFO) closure have been developed to close the pathway for thrombi that potentially embolize to the brain. In this way, adequate prevention against ischemic stroke may be provided without significantly increasing the bleeding risk. Clinical evidence from randomized controlled trials and a large multicenter registry supports the efficacy of LAAO to prevent ischemic stroke in AF patients for whom OAC is less suitable. Observational data suggest that LAAO may be more beneficial than medical therapy in the treatment of AF patients after an intracerebral hemorrhage (ICH), and initiatives are undertaken to further explore the effect of LAAO in this population. Long-term follow-up of patients who had a cryptogenic stroke and underwent PFO closure shows the beneficial effect of this strategy to prevent recurrent ischemic stroke. While device-based therapies are inevitably associated with the risk of acute, peri-procedural safety events, their relative benefits over medical treatment may become increasingly important at longer-term follow-up, given the steadily accumulating lifetime bleeding risk of long-term anticoagulation. Overall, device-based cardiac occlusion therapies may be justified for the prevention of ischemic stroke in AF patients with a high bleeding risk and relatively young cryptogenic stroke patients with evidence of a PFO.