Factor VIIa (FVIIa) is the enzyme that triggers activation of the clotting cascade that eventually leads to fibrin deposition and platelet activation. Association of FVIIa with its cellular receptor, tissue factor (TF), which greatly increases FVIIa enzymatic activity, is essential for the effective initiation of the coagulation pathway. FVIIa also complexes with endothelial cell protein C receptor (EPCR), but this association does not increase the enzymatic activity of FVIIa. This article reviews current knowledge of FVIIa interaction with TF and EPCR on cell surfaces with a specific focus on how these interactions may contribute to FVIIa and TF clearance, thereby regulating TF-FVIIa activity.