HCMV lytic DNA replication is complex and highly regulated. The cis-acting lytic origin of DNA replication (oriLyt) contains multiple repeat motifs that comprise two main functional domains. The first is a bidirectional promoter element that is responsive to UL84 and IE2. The second appears to be an RNA/DNA hybrid region that is a substrate for UL84. UL84 is required for oriLyt-dependent DNA replication along with the six core proteins, UL44 (DNA processivity factor), UL54 (DNA polymerase), UL70 (primase), UL105 (helicase), UL102 (primase-associated factor) and UL57 (single-stranded DNA-binding protein). UL84 is an early protein that shuttles from the nucleus to the cytoplasm, binds RNA, suppresses the transcriptional activation function of IE2, has UTPase activity and is proposed to be a member of the DExH/D box family of proteins. UL84 is a key factor that may act in concert with the other core replication proteins to initiate lytic replication by altering the conformation of an RNA stem loop structure within oriLyt. In addition, new data suggests that UL84 interacts with at least one member of the viral replication proteins and several cellular encoded proteins.