Sexually transmitted infections (STIs) caused by viruses, including HSV-2, HIV-1, HPV, are among the most prevalent infectious diseases worldwide and a major cause of morbidity and mortality. Despite decades of effort, the attempts to develop efficacious vaccines against viral STIs have failed repeatedly, with the exception of the recent HPV vaccine. Given the higher prevalence rates of STIs in women, it is becoming clear that a better understanding of gender-specific differences in STIs may be critical for the development of preventative strategies for these diseases. In order to gain this insight, it is important to examine the distinct microenvironment of the female reproductive tract, the site of primary infection, since it can significantly influence the outcome of infection. An important biological factor in the female reproductive tract is the presence of female sex hormones, estrogen and progesterone, which are produced endogenously primarily by the ovaries and commonly provided exogenously via the use of hormonal contraceptives. Here we review our current knowledge of the role played by the female sex hormones in regulating susceptibility and immune responses to viral sexually transmitted infections and whether this could contribute to higher prevalence of STIs in women. Manipulating the microenvironment of the female genital tract with sex hormones may contribute to the development of improved immunization strategies against sexually transmitted infections.