© Springer Science+Business Media, LLC 2009. All rights reserved. DNA viruses, as well as their host cells, require a DNA-dependent DNA polymerase to faithfully replicate their genomes. Viruses with small DNA genomes, such as papillomaviruses and polyomaviruses, have a limited coding capacity and utilize mainly the host replication machinery for their genome amplification. In contrast, large DNA viruses encode a specific polymerase equipped with a proofreading 3′-5′-exonuclease activity and other replication proteins that assure the replication of their genomic information. As a critical component of the viral replication machinery, viral DNA polymerases are the specific target of a number of antiviral drugs currently used to inhibit viral replication. Most antiviral drugs approved by the US Food and Drug Administration (FDA) inhibit viral genome replication, nearly all of these inhibit a DNA polymerase and most of these drugs are nucleoside analogs. FDA-approved inhibitors of viral polymerases target certain human herpesviruses, the retrovirus HIV (human immunodeficiency virus) and the hepadnavirus HBV (hepatitis B virus). This chapter focuses on the description of viral DNA polymerase inhibitors, whether currently approved or candidate drugs, that are particularly active against herpesviruses.