Abstract: Viruses have evolved to commandeer their host cells to optimize their infections, and host organisms have evolved many mechanisms to resist them. Foreign or non-self DNA is a threat, and all cells have mechanisms to resist them. For eukaryotic cells, this involves epigenetic silencing of the invading viral genome. The herpesviruses contain no histones associated with their virion DNA genomes, and when the viral DNA genomes enter the nucleus, cellular mechanisms load heterochromatin on viral genes to silence them. I will discuss the mechanisms that HSV gene products use to reverse the epigenetic silencing of their genome during lytic infection and to further silence their genome during latent infection. These studies also reveal that mammalian cells use normal epigenetic mechanisms for sensing and silencing foreign DNA such as viral and plasmid DNA.