The F4/80 monoclonal antibody has been used widely as a marker for mouse macrophages. The antigen (Ag) recognized by the antibody has been characterized as a member of the epidermal growth factor (EGF)-transmembrane 7 (TM7) family, although the function of the molecule has remained elusive. A recent study provides evidence for a role of the F4/80 molecule in the induction of immunological tolerance. This study appears to provide clear evidence for a role of the F4/80 molecule in the immune system, however, what does it really tell us about the activities of the F4/80 molecule?