(A), The intrauterine environment during human pregnancy. Embryonic structures include the villous tree of the human hemochorial placenta and the umbilical cord, which transfers blood between the placenta and the fetus. (B), An overview of a single placental villus. Extravillous trophoblasts invade and anchor the placenta to the maternal decidua and to the inner third of the myometrium. The villous tree consists of both floating and anchoring villi. Multinucleated syncytiotrophoblasts overlie the surfaces of the villous tree and are in direct contact with maternal blood, which fills the intervillous space (IVS) once the placenta is fully formed. Mononuclear cytotrophoblasts are subjacent to the syncytiotrophoblasts and the basement membrane of the villous tree, and serve to replenish the syncytiotrophoblast layer throughout pregnancy. (C), In the work presented here, we show that syncytiotrophoblasts release IFNλ1 that can act in both autocrine and paracrine manners to induce ISGs, which protect against ZIKV, and other viral infections. The paracrine function of IFNλ could work locally within the direct maternal-fetal compartment, or might circulate more systemically to act on other maternal target cells.