Once the HCMV genome is delivered to the nucleus, IE gene expression ensues. RNA pol II transcription machinery transcribes IE as well as all other protein-coding and noncoding RNAs made from the HCMV genome. Regulation of viral gene expression occurs via two broad strategies: (1) viral as well as cellular factors that directly influence the transcription machinery by binding to promoter/enhancer elements directly (transcription factors) or through interactions with other proteins (adaptors) (2) viral factors that alter chromatin remodeling by regulating the opposing activities of histone acetyl transferases (HATs) acting together with demethylases and histone deacetylases (HDACs) and methylases. HDAC-dependent repression of viral IE gene expression, in particular, is a cell-intrinsic host defense mechanism that must be defused before productive replication can ensue. Epigenetic regulation is important in permissive cells, even though the viral genome does not take on a recognizable chromatin structure, and also during latency, where viral genomes take on an organized chromatin arrangement and viral HDAC inhibitors can drive reactivation.