Summary. Understanding the mechanism of action of normal hemostasis and how the bypassing agents recombinant activated factor VII (rFVIIa; NovoSeven) and plasma-derived activated prothrombin complex concentrate (Factor Eight Inhibitor Bypassing Agent [FEIBA]) control abnormal bleeding is imperative for healthcare professionals who treat patients with hemophilia and other bleeding disorders. A cell-based model has improved our understanding of in vivo mechanisms of hemostasis and the basis of the bleeding tendency in hemophilia. Bypassing agents do not restore the normal pathways of hemostasis in hemophilia, but rather boost thrombin generation in spite of a lack of platelet surface FVIIIa–FIXa (‘tenase’) activity. Thus, the common clinical laboratory coagulation assays do not reflect the clinically relevant hemostatic activity of bypassing agents, and no validated assay is available with which to measure the in vivo efficacy of these agents or predict individual patient responses to treatment. Global hemostasis assays measuring overall coagulation capacity have potential for assessment of the effects of bypassing agents. This review will focus on the mechanisms of clotting and their relationship to understanding the mechanisms of action of the bypassing agents in vivo and the methodologies that are emerging to monitor the clinical efficacy of bypassing agent therapy.