The mucosal immune system in the human female reproductive tract is unique and distinct from all other mucosal surfaces. Consisting of the innate and adaptive immune systems, immune protection has evolved to meet the constraints of protecting against potential viral, bacterial and fungal pathogens while ensuring reproductive success of an allogeneic conceptus. In this review, we focus on our current understanding of role of sex hormones in regulating mucosal immunity throughout the female reproductive tract. Consisting of several compartments including the Fallopian tubes, uterus, endocervix, ectocervix, and vagina, each site is precisely and independently regulated by the ovarian production of estradiol and progesterone. These hormones act both directly and indirectly through cytokines, chemokines, and growth factors, to regulate immune cell phenotype and function as well as immune protection in reproductive tract secretions. Understanding the immune system in the female reproductive tract is essential for the development of appropriate immunoprophylaxis to regulate fertility, deal with those challenges that prevent successful pregnancies, and control sexually transmitted diseases that compromise reproductive health and the lives of women and children worldwide.