Anticoagulants and anti-platelet drugs are essential and widely used therapeutic tools in modern cardiovascular medicine. However, the initiation of anti-thrombotic therapies, their termination, or transient discontinuation (e.g. for surgical procedures) are critical steps which have to be managed appropriately. In the near future, several novel irreversibly or reversibly acting anti-thrombotic drugs with direct and indirect mechanisms of action, will be approved. Their prescription will require a deep understanding of their pharmacodynamics and -kinetics. In addition, pharmacogenomic issues will become increasingly important for the optimization of individual therapeutic strategies. This review summarizes clinically relevant principles and discusses them in the light of the assessment of the individual thrombotic and bleeding risks.