The current repertoire of approved anti-herpesviral drugs consists primarily of nucleoside analogues that inhibit viral replication by targeting the virus-encoded DNA polymerase. This class of agents has been critical in controlling infections by herpes simplex, varicella zoster, and cytomegalovirus. However, because nucleoside analogues share a similar mechanism of action, treatment options are limited once resistance develops. This becomes an important medical issue with respect to the treatment of disease caused by resistant viral strains, particularly in immunocompromised individuals. Furthermore, several of the currently available therapies can result in mild to severe side effects making the discovery of less toxic drugs desirable. Efforts over the last decade have focused on the identification and development of improved therapies including less toxic compounds with novel mechanisms of action. Here we review the progress that has been made in targeting the DNA packaging and encapsidation process as a novel target for chemotherapy. Several recently identified compounds may warrant further development as a medically important group of herpesviral encapsidation inhibitors.