CD97 is a member of the EGF-TM7 family of adhesion G protein-coupled receptors (GPCRs) broadly expressed on leukocytes. CD97 interacts with several cellular ligands via its N-terminal epidermal growth factor (EGF)-like domains. To understand the biological function of CD97, monoclonal antibodies (mAbs) specific for individual EGF domains have been applied in a variety of in vivo models in mice, which represent different aspects of innate and adaptive immunity. Targeting CD97 by mAbs inhibited the accumulation of neutrophilic granulocytes at sites of inflammation thereby affecting antibacterial host defense, inflammatory disorders and stem cell mobilization from bone marrow. Interestingly, targeting CD97 did not impact antigen-specific (adaptive response) models such as delayed type hypersensitivity (DTH) or experimental autoimmune encephalomyelitis (EAE). However, collagen-induced arthritis (CIA), a model for rheumatoid arthritis, was significantly ameliorated suggesting therapeutic value of CD97 targeting. CD97-deficient mice are essentially normal at steady state except for a mild granulocytosis, which increases under inflammatory conditions. Comparison of the consequences of antibody treatment and gene targeting implies that CD97 mAbs actively inhibit the innate response presumably at the level of granulocyte or macrophage recruitment to sites of inflammation. Based on the collected data, we propose that the CD97 mAbs either activate CD97-mediated signal transduction via a yet unknown mechanism or act by inducing CD97 internalization, making CD97 unavailable for binding to its ligands and thereby blocking recruitment of neutrophils and possibly macrophages.