Purpose: The objective of this review was to summarize the recent literature describing the current burden of disease due to herpesviruses in the antiviral and transplant era; describe mechanisms of action of antiviral agents and the development of resistance; summarize the literature of recent antiviral agents brought to market as well as agents under development; and to present literature on future strategies for herpesvirus therapeutics. Methods: An extensive search of the medical literature related to antiherpesviral therapy was conducted to compose this narrative review. Literature searches were performed via PubMed and ultimately 137 articles were included as most relevant to the scope of this article. Findings: Herpesviruses are a family of DNA viruses that are ubiquitous throughout human populations and share the feature of establishing lifelong infections in a latent phase with the potential of periodic reactivation. With the exception of herpes simplex virus, varicella zoster virus, and Epstein-Barr virus, which have a significant disease burden in individuals with normal immune function, the morbidity and mortality of the remaining viruses are primarily associated with the immunocompromised host. Over the last half-century, several agents have been tested in large randomized, placebo-controlled trials that have resulted in safe and effective antiviral agents for the treatment of many of these infections. Implications: With increasing use of antiherpesviral agents for extended periods, particularly in immunocompromised hosts, the emergence of resistant viruses has necessitated the development of newer agents with novel targets and better side-effect profiles.