The process of virus entry accomplishes the delivery of the viral genetic information into the cell so that replication can take place. Entry of enveloped viruses into mammalian cells requires that the virus attach to the host cell surface through an interaction between an envelope component and a cellular molecule that serves as a receptor. After attachment, the virus must cross the plasma membrane during a phase of the life cycle termed penetration . For enveloped viruses, a fusion reaction occurs between the viral envelope in either the endosomal membrane or the plasma membrane. In simple viral systems that have one or two envelope glycoproteins, generally, a single, specific interaction between a viral protein and a cellular constituent is necessary and sufficient to result in infection. The herpesviruses, including human cytomegalovirus (HCMV), are structurally much more complex and often exhibit broad, diverse cellular tropism. Thus, all evidence to date points to the involvement of multiple cellular and viral proteins with overlapping or compensatory mechanisms possibly responsible for entry into specialized cell types.