The risk of bleeding associated with antithrombotic and fibrinolytic therapy depends on factors that are specific for the drugs and the patients. In this narrative review, we describe the most important risk factors for bleeding for each class of drugs. Pertinent examples are recent initiation of therapy with vitamin K antagonists, low-molecular-weight heparins, and renal dysfunction, and higher dose of aspirin. However, for every class of drug, there are also examples that are more controversial. Knowledge of these risk factors helps to weigh the risk and benefit in the selection of therapy in individual patients. Moreover, some risk factors can be modified or avoided if they are recognized.