The continued presence of bacterial and viral antigens in the lumen of the vagina coupled with the periodic presence of antigens in the lumena of the upper reproductive tract provide an ongoing challenge that can compromise female reproductive health and threaten life. Separating underlying tissues from luminal antigens, polarized epithelial cells of the cervix, uterus and Fallopian tubes have evolved to protect against potential pathogens. Once thought to function exclusively by providing a crucial barrier, mucosal epithelial cells are now known to function as sentinels that recognize antigens, respond in ways that lead to bacterial and viral killing, as well as signal to underlying immune cells when pathogenic challenge exceeds their protective capacity. Unique to epithelial cells of the female reproductive tract is the regulatory control of the female sex hormones. Acting both directly and indirectly through underlying stromal cells, estradiol and progesterone regulate epithelial cell innate and adaptive immune functions to protect against potential pathogens while providing an environment that supports an allogeneic fetus. In this article, we will outline how polarized epithelial cells function as the first line of defense against potential pathogens in the female reproductive tract.