Human cytomegalovirus (HCMV) is a pervasive β-herpesvirus that causes lifelong infection. The lytic replication cycle of HCMV is characterized by global organelle remodeling and dynamic virus–host interactions, both of which are necessary for productive HCMV replication. With the advent of new technologies for investigating protein-protein and protein–nucleic acid interactions, numerous critical interfaces between HCMV and host cells have been identified. Here, we review temporal and spatial virus–host interactions that support different stages of the HCMV replication cycle. Understanding how HCMV interacts with host cells during entry, replication, and assembly, as well as how it interfaces with host cell metabolism and immune responses promises to illuminate processes that underlie the biology of infection and the resulting pathologies.