Essential to hemostasis is the interaction of factor IXa with factor VIIIa. Recent studies indicate that helix-330 in the protease domain of factor IXa provides a critical binding site for factor VIIIa. Although weaker interactions cannot be ruled out, a primary role of the EGF1 domain of factor IXa in this context may be to serve as a spacer in properly positioning the factor IXa protease domain for optimal interaction with factor VIIIa. The role of the Gla domain, as well as of the EGF2 domain of factor IXa, in binding to factor VIIIa is not clear. The region of factor VIIIa that interacts with the protease domain of factor IXa is quite possibly located in the A2 domain. Furthermore, it should be noted (Table 1) that the corresponding helix residues in factor VIIa bind to tissue factor, and, in factor Xa, they are involved in binding to factor Va. Thus, a common function of this helix (162 in chymotrypsin numbering) in several blood coagulation proteases may be to serve as an anchoring point for the respective cofactor.