In addition to its well-characterized role in hemostasis, fibrin(ogen) has been proposed to be a central regulator of the inflammatory response. Multiple in vitro studies have demonstrated that this hemostatic factor can alter leukocyte function, including cell adhesion, migration, cytokine and chemokine expression, degranulation, and other specialized processes. One important link between fibrin(ogen) and leukocyte biology appears to be the integrin receptor α_Mβ₂/Mac-1, which binds to immobilized fibrin(ogen) and regulates leukocyte activities. Although it is well established that fibrin(ogen) is a ligand for α_Mβ₂, the precise molecular determinants that govern this interaction are only now becoming clear. A novel line of mice expressing a mutant form of fibrinogen (Fibγ^390_396A) has revealed that γ chain residues 390–396 are important for the high-affinity engagement of fibrinogen by α_Mβ₂ and leukocyte unction in vivo. Fibrinogen γ^390–396A failed to support α_Mβ₂-mediated adhesion of primary neutrophils, monocytes, and macrophages, and mice expressing this fibrinogen variant were found to exhibit a major defect in the host inflammatory response following acute challenges. Most notably, Fibγ^390–396A mice display a profound impediment in Staphylococcus aureus elimination by leukocytes following intraperitoneal inoculation. These findings have positively established the physiological importance of fibrin(ogen) as a ligand for α_Mβ₂ and illustrate that the fibrin(ogen) γ chain residues 390–396 constitute a critical feature of the α_Mβ₂ binding motif. Finally, the Fibγ^390–396A mice represent a valuable system for better defining the contribution of fibrin(ogen) to the inflammatory response in the absence of any confounding alteration in clotting function.