The discoveries of the factor V Leiden mutation and the prothrombin gene variant 20210 in the last decade have markedly contributed to the understanding of the molecular pathophysiology of inherited risk factors for thrombophilia. Population studies in the adult literature have shown that although the overall prevalence of these defects is low, affected individuals are at increased risk of thrombosis particularly if acquired risk factors for thrombosis are also present. The use of combined hormonal oral contraceptive pills is a well-known acquired risk factor, and recent studies have shown significant increased risk of thrombosis for women who carry the factor V Leiden mutation and use oral contraceptive pills. Despite this significant increased risk, mass screening of asymptomatic women for factor V Leiden prior to prescribing oral contraceptive pills is not a cost-effective use of health care dollars and could result in unnecessarily preventing many women from the contraceptive and noncontraceptive benefits of this medication. Instead, clinicians can use thoughtful screening questions to identify potentially high-risk patients for thrombophilia and consider testing for inherited risk factors on a case-specific basis.