Heterosexual spread of HIV remains the major risk factor for transmission worldwide. Genital secretions from the infected partner contain both cell-free and cell-associated virus. Although the exact mechanism of heterosexual transmission is unknown, genital virus plays an important role. Decreasing the genital shedding of HIV is an important step in slowing the spread of the disease. Recent studies have shown that antiretroviral penetration into the genital tract varies by class and that antiretroviral therapy significantly decreases HIV levels. Compartmentalization between the blood and genital tract is based on viral load levels, resistant variants, viral diversity, and coreceptor usage. HSV-2, lack of lactobacilli, and plasma cell endometritis increased HIV genital shedding. HSV-2 suppressive therapy significantly reduces plasma and genital tract viral load. Data are conflicting on the effect of hormonal contraception on HIV genital shedding. Further studies are needed to translate these findings into decreased spread on a population level.