Expression of microRNAs appears to be ubiquitous among members of the herpesvirus family, suggesting that small RNAs play a fundamental role in the biology of these viruses. Human cytomegalovirus, a member of the beta herpesvirus subfamily, express at least 22 microRNAs and studies by our group and others have sought to understand the functional role of these small regulatory RNAs in the context of viral infection. Although in the early stages, research suggests that HCMV microRNAs, and herpesvirus microRNAs in general, may play important roles in the establishment and maintenance of viral latency. Latency and subsequent reactivation represent crucial aspects associated with the pathogenesis of herpesviruses. Investigating the role of viral microRNAs will provide a greater understanding of the underlying mechanisms involved in latency, thereby establishing the foundations for improved treatment and therapies. In this chapter we will review the evidence supporting a central role of microRNAs in the establishment and maintenance of Human cytomegalovirus latency and how this relates to potential future medical interventions.