While many viral infections are limited and eventually resolved by the host immune response or by death of the host, other viruses establish long-term relationships with the host by way of a persistent infection, that range from chronic viruses that may be eventually cleared to those that establish life-long persistent or latent infection. Viruses infecting hosts from bacteria to humans establish quiescent infections that must be reactivated to produce progeny. For mammalian viruses, most notably herpesviruses, this quiescent maintenance of viral genomes in the absence of virus replication is referred to as latency. The latent strategy allows the virus to persist quiescently within a single host until conditions indicate a need to reactivate to reach a new host or, to re-seed a reservoir within the host. Here, I review common themes in viral strategies to regulate the latent cycle and reactivate from it ranging from bacteriophage to herpesviruses with a focus on human cytomegalovirus (HCMV). Themes central to herpesvirus latency include, epigenetic repression of viral gene expression and mechanisms to regulate host signaling and survival. Critical to the success of a latent program are mechanisms by which the virus can “sense” fluctuations in host biology (within the host) or environment (outside the host) and make appropriate “decisions” to maintain latency or re-initiate the replicative program. The signals or environments that indicate the establishment of a latent state, the very nature of the latent state, as well as the signals driving reactivation have been topics of intense study from bacteriophage to human viruses, as these questions encompass the height of complexity in virus-host interactions—where the host and the virus coexist.