Oral anticoagulant therapy for venous thromboembolism is very effective. When oral anticoagulants are managed well, the risk of recurrence is approximately 2 per 100 patient-years. The main reasons for a breakthrough event are underlying disease and subtherapeutic drug levels. The most common underlying disease that results in recurrence on treatment is cancer. Subtherapeutic drug levels can be caused by poor adherence to the drug regimen, interactions with other drugs or food, or inappropriate dosing. It is important to investigate and understand the cause whenever such an event occurs and to improve management of anticoagulants thereby avoiding further recurrences. Here we present 4 illustrative cases together with a discussion of the underlying pathology. Whereas the mechanisms are usually quite well understood, the management of further anticoagulation after a breakthrough event is based on minimal or no clinical trial evidence.