Normal pregnancy is associated with alterations of the hemostatic system toward a hypercoagulable state. Elevated markers of coagulation and fibrinolytic system activation, such as D-dimer, indicate increased thrombin activity and increased fibrinolysis following fibrin formation throughout pregnancy. Testing for D-dimer in pregnant women could be useful for the diagnosis and prediction of a venous thromboembolic event or pregnancy-related complications and for monitoring antithrombotic treatment. This approach, however, is hampered by the fact that even an uncomplicated pregnancy in healthy women is accompanied by a substantial increase of D-dimer. Thus, prior to clinical application reference values of D-dimer according to gestational age need to be validated. A substantial increase of D-dimer during pregnancy is seen despite thromboprophylaxis with low-molecular-weight heparin (LMWH), indicating that further studies are needed to evaluate monitoring of LMWH during pregnancy and to investigate the optimal beginning and dose of LMWH thromboprophylaxis in pregnant women.