Abstract Immune cells at the maternal/fetal interface play dual roles of orchestrating immune tolerance required for pregnancy maintenance, while also protecting against placental pathogens, such as cytomegalovirus (CMV). Specialized inhibitory immune cells, known as natural killer (NK) cells, are predominant and dynamic immune cells populating the decidua throughout gestation. Yet, there is a major gap in our understanding of the role of NK cells in protection of the fetus against immune rejection and pathogen invasion. The role of NK cells, including recently identified cytomegalovirus (CMV)-specific memory NK cells, in the interplay between fetal tolerance and protection against congenital CMV transmission is poorly defined. This study aims to define the role of maternal NK cell populations in regulation of fetal tolerance and protection against placental CMV transmission in the setting of chronic maternal CMV infection. Our group is uniquely equipped to dissect the immunologic functions at the maternal-fetal interface with significant expertise in both a nonhuman primate (NHP) model of pregnancy and placental CMV transmission as well as investigations of immune cells at the maternal-fetal interface in human placenta and cord blood. The NHP model affords the opportunity to study the immunology and physiology of pregnancy across the gestational stages through elective fetal harvest and access to the immune cells at the maternal-fetal interface, as well as validated strategies for peripheral and tissue depletion of effector NK cells in vivo. We hypothesize that maternal NK cells are critical to both pregnancy maintenance and prevention of CMV reactivation in early pregnancy. Understanding this intersection between maintaining immune tolerance while protecting against placental pathogens is critical to developing immune-based strategies to reduce the morbidity and mortality resulting from adverse pregnancy outcomes.