Herpesviruses are a large group of DNA viruses that infect a wide range of animal hosts, with eight known to infect humans. Herpes simplex virus type 1 (HSV-1) is a ubiquitous virus that infects over 60% of the human population causing a range of outcomes including asymptomatic infection, recurring cold sores, blindness, or encephalitis. We are interested in determining how herpesviruses manipulate host cells to simultaneously escape DNA damage and other host responses while adapting host factors for use in viral processes. To identify host proteins involved in viral processes, we developed a new approach to purify HSV-1 DNA from infected cells for the identification of viral genome-associated proteins using mass spectrometry. This allowed us for the first time to comprehensively identify the viral and host proteins that interact with HSV-1 DNA from the time the viral genome enters into the nucleus through packaging of newly replicated viral DNA into nascent virions. We discovered that select host transcription, chromatin remodeling, DNA replication, and DNA repair proteins associate with HSV-1 genomes in a temporal manner and that protein recruitment is blocked in the absence of key viral factors. We are currently using genetic, proteomic, imaging, and high throughput sequencing approaches to define the functions of viral genome associated host proteins in the regulation of viral genome structure, gene expression, DNA replication, and DNA repair.