Biological strategies for interrupting transmission of human immunodeficiency virus (HIV) type 1 should be directed at reducing infectiousness of and susceptibility to HIV-1. Potential antiretroviral interventions include reducing the likelihood of transmission of HIV-1 by reducing HIV-1 load in the blood and genital tract of HIV-1--infected person, prophylaxis after high-risk exposure, and pre-exposure prophylaxis for very high risk populations. Antiviral treatment of herpes simplex virus (HSV) type 2, the most common cause of genital ulcers, should be evaluated as a strategy for HIV-1 infection prevention by reducing infectiousness of and susceptibility to HIV-1, on the basis of biological and epidemiological data indicating that HSV-2 facilitates transmission and acquisition of HIV-1. The rationale for antiretroviral and HSV-2-specific interventions and studies to test these strategies are described.