The use of oral contraceptives (OCs) has been known for many years to affect significantly almost all hemostatic parameters, but the challenge to relate these changes in a meaningful way to OC-induced increased venous thrombotic risk has not been met. New insights indicate that at least part of the answer can be found in the net effect of OC use on the efficacy with which the protein C pathway down-regulates thrombin formation. During OC use the (blood) plasma of a woman becomes resistant to the anticoagulant action of activated protein C (APC). The extent of this so-called acquired APC resistance as determined in a thrombin generation-based assay correlates remarkably well with the risk increases observed in clinical studies. Recent evidence indicates that the prothrombotic effect of the estrogen component ethinylestradiol in combined OC is counteracted by the progestagen component present in these preparations and that third-generation progestagens such as desogestrel or gestodene are less efficient with respect to this than the second-generation progestagen levonorgestrel.