This discussion considers several important hypercoagulable states that predispose patients to venous, and in some instances, arterial thrombosis, focusing on activated protein C resistance/factor V Leiden, prothrombin G20210A, deficiencies of protein C, protein S or antithrombin, and antiphospholipid antibodies. The discussion includes the incidence of each hypercoagulable condition, the magnitude of the thrombotic risk it poses and synergistic interactions among the various hypercoagulable conditions. Salient advances in understanding the molecular pathogenesis of each condition are presented and discussed in the context of the interpretation and clinical utility of current laboratory testing and identifying potential targets of future testing. Finally, recommendations for laboratory testing are summarized.