OBJECTIVE: To review the first generation of antiviral agents (e.g., idoxuridine, amantadine, vidarabine) that paralleled discovery of antineoplastic agents. DATA SOURCES: A MEDLINE search (1962 to 1996) of the English-language literature pertaining to antiviral agents was performed. DATA EXTRACTION: All articles were considered for this review. Pertinent references on antiviral therapy, as judged by the author, were selected. DATA SYNTHESIS: Acyclovir, the first second-generation antiviral agent, has a known selective mechanism of action and provides the model for development of future antiviral therapies. Despite the safety and clinical value of acyclovir, therapy does not prevent establishment of latency or decrease frequency of occurrences, resistance has been documented, and outcome is frequently poor. With the emergence of the HIV/AIDS epidemic, several antiretroviral agents have been developed and approved. However, none of the four available nucleoside analogs provides a cure. CONCLUSIONS: Viral resistance has emerged as an important component of antiviral therapy. Improved therapies for cytomegalovirus are needed. Several new therapies for herpes zoster, including prodrugs, are licensed or in Phase III clinical trials. Future directions include the use of molecular biologic techniques to identify enzymes unique to viral replication and to accelerate diagnosis of vital diseases.