Anticoagulation is a potent therapy that can cause major and even fatal hemorrhage. Therefore, it is always necessary to balance the benefits and harms carefully. These effects differ with the diseases and patient characteristics. For many conditions, guidelines give clear recommendations regarding the duration of anticoagulation. For venous thromboembolism, there is a greater challenge to assess the net benefit of extended anticoagulation in the individual case. There are also conditions with very limited data and therefore no evidence-based recommendations on duration of treatment. This review focuses on the evaluation of (1) disease conditions as high or low risk according to the consequences of thromboembolic events, (2) the durability of the risk, and (3) the magnitude of the bleeding risk. The balancing of thrombotic versus bleeding risk is based on some typical patient scenarios. Examples of risk prediction tools are also provided.