The mucosal immune system in the upper female reproductive tract is uniquely prepared to maintain a balance between the presence of commensal bacteria, sexually transmitted bacterial and viral pathogens, allogeneic spermatozoa, and an immunologically distinct fetus. At the center of this dynamic system are the epithelial cells that line the Fallopian tubes, uterus, cervix and vagina. Epithelial cells provide a first line of defense that confers continuous protection, by providing a physical barrier as well as secretions containing bactericidal and virucidal agents. In addition to maintaining a state of ongoing protection, these cells have evolved to respond to pathogens, in part through Toll-like receptors (TLRs), to enhance innate immune protection and, when necessary, to contribute to the initiation of an adaptive immune response. Against this backdrop, epithelial cell innate and adaptive immune function is modulated to meet the constraints of procreation. The overall goal of this review is to focus on the dynamic role of epithelial cells in the upper reproductive tract, with special emphasis on the uterus, to define the unique properties of these cells as they maintain homeostasis in preparation for successful fertilization and pregnancy while at the same time confer protection against sexually transmitted infections, which threaten to compromise womens reproductive health and survival. By understanding the nature of this protection and the ways in which innate and adaptive immunity are regulated by sex hormones, these studies provide the opportunity to contribute to the foundation of information essential for ensuring reproductive health.