Human herpesviruses are common human pathogens associated with a variety of diseases. Most of the currently available antiviral agents used in the treatment of herpesviruses inhibit the same target, the viral DNA polymerase. Although these drugs are effective, several drawbacks are associated with their use, including toxicity and emergence of drug resistance. In order to fulfill the unmet medical needs in the treatment of herpesvirus infections, development of new drugs which target other mechanism(s) of currently available anti-herpesviral agents will be needed. This review article focuses on the latest and potential drug targets of herpesviruses and their target validation.