Transcatheter structural heart interventions, including aortic, mitral and tricuspid valve replacement or repair, and patent foramen ovale, atrial septal defect, and left atrial appendage closure, have dramatically expanded over the past two decades, providing substantial improvements in both clinical outcomes and quality of life. These interventions are performed in a high-risk patient population, which is at risk for both thrombotic and bleeding complications. The introduction of prosthetic devices into the arterial or venous circulation under heterogeneous hemodynamic conditions inevitably increases the risk for thrombotic events and thromboembolic complications. Consequently, the selection of antithrombotic therapy (AT) regimen and its duration is complex and should be tailored to each patient’s risk profile, balancing the expected risk and benefits. This state-of-the-art review critically examines the thrombotic risks inherent to transcatheter structural heart interventions, synthesizes available evidence and current guidelines recommendations on antithrombotic management, and defines persisting gaps in knowledge while discussing the most relevant ongoing clinical trials.