Herpes simplex viruses (HSV) can undergo a lytic infection in epithelial cells and a latent infection in sensory neurons. During latency the virus persists until reactivation, which leads to recurrent productive infection and transmission to a new host. How does HSV undergo such different types of infection in different cell types? Recent research indicates that regulation of the assembly of chromatin on HSV DNA underlies the lytic versus latent decision of HSV. We propose a model for the decision to undergo a lytic or a latent infection in which HSV encodes gene products that modulate chromatin structure towards either euchromatin or heterochromatin, and we discuss the implications of this model for the development of therapeutics for HSV infections.