Analyses of small RNA expression profiles have revealed that several DNA viruses—including particularly, herpesviruses—express high levels of multiple viral microRNAs (miRNAs) in infected cells. Here, I review our current understanding of how viral miRNAs influence viral replication and pathogenesis and discuss how viruses reshape the pattern of cellular miRNA expression. Indeed, viruses are now known to both activate and repress the expression of specific cellular miRNAs, and disrupting this process can perturb the ability of viruses to replicate normally. In addition, it is now clear that virally encoded miRNAs play a key role in inhibiting antiviral innate immune responses and can also promote cell transformation in culture. While our understanding of how viruses interact with miRNAs remains somewhat rudimentary, it is nevertheless already clear that these interactions can play a critical role in mediating viral pathogenesis and therefore may represent novel and highly specific targets for therapeutic intervention.