Viral infection is initiated by the attachment of the virus to the appropriate host cells. This process involves a series of dedicated virion proteins that have evolved to specifically recognize one, or a small number, of cell-surface molecules. Although a number of virus–host attachment mechanisms involve direct protein–protein interactions, carbohydrate molecules such as sialic acids (SAs) may also serve as receptor-binding determinants. The binding of viral envelope glycoproteins to carbohydrates on cell membranes plays a significant role in infection by many viruses. In general, the glycoproteins of several lipid-enveloped viruses, including orthmyxoviruses (influenza A, B, and C), toroviruses, and coronaviruses, have three important functions: to recognize the receptor on the cell surface, to mediate viral fusion with the cell membrane, and to destroy the receptor. In the highly infectious influenza A and B viruses, the receptor-binding and membrane-fusion activities of cell entry are carried out by the glycoprotein hemagglutinin (HA) (Fig. 1a). The receptor-destroying enzyme (RDE) activity important for virus release is conducted by the glycoprotein/enzyme neuraminidase (NA). In influenza C virus, a single glycoprotein, the hemagglutinin-esterase-fusion (HEF) protein, possesses all three functions. For a number of toroviruses and group 2a coronaviruses, the glycoprotein hemagglutinin esterase (HE) has both receptor-destroying and receptor-binding activities. However, the receptor-binding activity of HE is considered accessory to that of the spike protein (S), a receptor-binding and fusion protein (Fig. 1 b). Our understanding of the structure, mechanism, and evolution of HA, HEF, NA, and S at the molecular level has increased substantially over the past two decades because of the availability of numerous x-ray structural models of these molecules in the unliganded or receptor-bound complexes. In contrast, a lack of detailed structural studies on HE has hindered our understanding of its function and evolution. In this issue of PNAS, Zeng et al. (1 …