Human herpesvirus-6 (HHV-6) is a T lymphotropic herpesvirus belonging to theBetaherpesvirinaesubfamily. HHV-6 was long classified into variants A and B (HHV-6A and HHV-6B); however, recently, HHV-6A and HHV-6B were reclassified as different species. The process of herpesvirus entry into target cells is complicated, and in the case of HHV-6A and HHV-6B, the detailed mechanism remains to be elucidated, although both viruses are known to enter cells via endocytosis. In this paper, (1) findings about the cellular receptor and its ligand for HHV-6A and HHV-6B are summarized, and (2) a schematic model of HHV-6A’s replication cycle, including its entry, is presented. In addition, (3) reports showing the importance of lipids in both the HHV-6A envelope and target-cell membrane for viral entry are reviewed, and (4) glycoproteins involved in cell fusion are discussed.