A number of important risk factors for the acquisition of HSV-2 have been established including female gender, black or Hispanic ethnic origin, HIV infection, age, and increased number of sexual partners. Transmission is influenced by a number of biological factors such as sexual behavior, use of condoms, duration of relationships, and knowledge of a partner's serologic status. Vertical transmission (transmission of HSV from mother to neonate) is potentially life-threatening; neonatal HSV infection is associated with significant morbidity and mortality. The valaciclovir transmission study provides evidence that an antiviral agent can interrupt the transmission of a viral sexually transmitted disease between serologically discordant sexual partners. This review explores the importance of the cofactors that affect transmission, and makes recommendations on considerations for the prophylactic use of antiviral agents for the prevention of transmission in other patient populations. © 2004 Elsevier B.V. All rights reserved.