The absolute dependence of herpes simplex virus (HSV) replication on HSV DNA polymerase and six other viral-encoded replication proteins implies that specific inhibitors of these proteins' functions would be potent antiviral agents. The only currently licensed anti-herpes simplex drug, acyclovir, is an inhibitor of HSV DNA polymerase and is widely held to block viral replication primarily by specifically inhibiting viral DNA replication. In spite of the substantial advance in HSV therapy in recent years through the introduction of acyclovir, this anti-HSV compound and most of the other compounds under pharmaceutical development are substrate analogs. Since antiviral drug resistance has become an issue of increasing clinical importance, the need for structurally unrelated agents which incorporate novel mechanisms of viral inhibition is apparent. Understanding the structure and function of herpesvirus DNA polymerase and its interaction with the other six essential replication proteins at the replication origin should assist us in designing the next generation of therapeutic agents. The sequences of these proteins have been deduced and the proteins themselves have been expressed and purified in a variety of systems. The current challenge, therefore, is to use the available information about these proteins to identify and develop new, exquisitely specific antiviral therapeutics. In this review, we have summarized the current approaches and the results of structure/function studies of the herpes virus proteins essential for DNA replication, with the goal of more precisely defining novel antiviral targets.