Following peak expression of major immediate early (MIE) regulatory proteins, the second class of early genes, delayed early (DE), become transcriptionally active independent of the host cell type. Although some DE gene products are produced in abundance from the start, most of the proteins and assorted miRNAs accumulate gradually. The DE period of viral replication continues until viral DNA synthesis initiates. DE genes are crucial for viral DNA synthesis and include several functions that become important later in infection for maturation and egress. Many DE genes have a substantial impact on replication when disrupted. DE gene products dispensable for replication in fibroblasts may contribute to modulation of the host cell and host animal response to infection. Several HCMV DE genes switch or add transcriptional start sites later in infection, which means that transcript levels represent the combined products of different kinetic classes of gene expression.