Primary infection of healthy individuals with human cytomegalovirus (HCMV) is usually asymptomatic and results in the establishment of a lifelong latent infection of the host. Although no overt HCMV disease is observed in healthy carriers, due to effective immune control, severe clinical symptoms associated with HCMV reactivation are observed in immunocompromised transplant patients and HIV sufferers. Work from a number of laboratories has identified the myeloid lineage as one important site for HCMV latency and reactivation and thus has been the subject of extensive study. Attempts to elucidate the mechanisms controlling viral latency have shown that cellular transcription factors and histone proteins influence HCMV gene expression profoundly and that the type of cellular environment virus encounters upon infection may have a critical role in determining a lytic or latent infection and subsequent reactivation from latency. Furthermore, the identification of a number of viral gene products expressed during latent infection suggests a more active role for HCMV during latency. Defining the role of these viral proteins in latently infected cells will be important for our full understanding of HCMV latency and reactivation in vivo.