Over the past two decades, the recognition of viral enzymes and proteins that can serve as molecular targets of drugs has revolutionized the treatment of viral infections. Beginning with acyclovir, a number of systemically administered agents which are both relatively safe and effective for the treatment of herpetic infections and human immunodeficiency virus (HIV) infections have become widely available. Because of increased numbers of herpes virus infections, as well as the rising epidemic of HIV infections, the ophthalmologist is, more likely than ever before to be involved in the treatment of severe and frequent ocular infections caused by herpes viruses. In addition, the acute retinal necrosis (ARN) syndrome has been demonstrated to be caused by herpes viruses and a once rare retinal infection caused by cytomegalovirus is common in patients with the acquired immunodeficiency syndrome (AIDS). In this article, four systemic antiviral drugs (Vidarabine, Acyclovir, Ganciclovir, and Foscarnet) that have demonstrated usefulness in the treatment of ophthalmic disease are reviewed in detail with regard to their mechanisms, applications, effectiveness, and side effects.