The role of semen in heterosexual transmission of the HIV-1 has been marginally viewed as an inert vehicle for the delivery of virus. However, studies from the field of reproductive biology have made it clear that seminal fluid is a complex and dynamic medium containing high concentrations of factors that play key roles in modulating the local immune response in the female reproductive tract during fertilization and embryogenesis. It is therefore strongly implied that the same seminal factors responsible for guiding the immune response in reproduction also play a role in male-to-female transmission of HIV-1. To begin to understand how these factors affect male-to-female HIV-1 transmission, multiple studies have comparatively profiled the contents of seminal fluid collected from uninfected and HIV-1-infected men. This review provides an overview of these studies, as well as a discussion of the potential impact of semen on HIV-1 transmission.