Recently, it has become clear that herpesviruses are unique among pathogenic virus families in that they express multiple virally-encoded microRNAs in latently and/or lytically infected cells. The large size of herpesvirus genomes, combined with the inability of most human herpesviruses to replicate in animals, has until recently limited our ability to examine the contribution of viral miRNAs to herpesvirus replication and pathogenesis in vivo. However, recent data, primarily obtained using model animal herpesviruses, suggest that viral miRNAs, while not required for lytic replication in culture, can nevertheless strongly enhance viral pathogenesis, including oncogenesis, in vivo and also promote the establishment of a reservoir of latently infected cells.