Transferrin receptor (TFR1) is a cell surface receptor that functions in iron binding and uptake, but is also hijacked by numerous viruses to gain entry into the cell. In this study, the authors reveal the details of an evolutionary arms race between TFR1 and two rodent virus families (arenaviruses and mouse mammary tumour virus) that has shaped the evolution of the host protein and of at least one of the viral proteins involved. They observed that, although most of the TFR1 protein sequence is highly conserved, the two areas that show signs of rapid evolution correspond to the two distinct virus-binding surfaces, indicating that evolution of this protein is shaped by two concurrent selective pressures. Consistent with an arms race, the TFR1-contacting residues of arenavirus glycoprotein were also found to be under selective pressure. Importantly, mutations in the rapidly evolving residues of TFR1 blocked viral binding and entry without affecting iron uptake.