Human cytomegalovirus is a ubiquitous human pathogen that is the leading viral cause of birth defects. It also causes significant morbidity and mortality in both chemically and virally immunosuppressed individuals. Recent studies have begun to elucidate the interplay between this virus and its host cell on a molecular level. The interactions begin upon contact with the cell membrane, involve multiple processes including cell signaling, cell-cycle control and immune response mechanisms, and culminate in a productive infection.