The female reproductive tract (FRT) is a unique mucosal environment that is exposed to and interacts with a variety of factors, including commensal bacteria, potentially pathogenic microbes, as well as sperm and semen. The upper part of the FRT, primarily the endometrium, also has the unique function of providing a supportive environment to allow implantation and growth of a semi-allogeneic fetus during pregnancy. These divergent functional demands must also be carried out in a cyclical environment altered by the female sex hormones estradiol and progesterone. Notably, the different components of the immune system at the FRT play an integral part in fulfilling these functions. Tissue epithelial cells and the innate immune system form the first line of defense against pathogens, while the adaptive immune system generates antigen-specific responses and provides long-lasting immunological memory. The immune system consists of a full repertoire of immune cells such as natural killer cells, macrophages, dendritic cells, neutrophils, innate lymphoid cells, T cells, and B cells, in addition to a number of soluble factors including mucus, antimicrobial peptides, and interferons. Herein, we describe the different components of the mucosal immune system in the FRT, as well as the multifaceted roles they play in the context of sexually transmitted infections (STIs), sex hormones, and the microbiota.