In eutherian organizms, the placenta acts as the key barrier between the maternal and fetal compartments and protects the developing fetus from the vertical transmission of viruses adn other microorganisms. The human placenta is unlike any other human organ. Given its critical role in protecting the fetus, it must function not only as a barrier and conduit between the maternal and fetal microenvironments, but must also act as an active immunological tissue that responds to microbes present in the maternal circulation. Within the human hemochorial placenta, the frontlines of fetal protection are the synctiotrophoblasts (SYNs), cells that cover the surface of the human placental villous trees. Very little is known about the cell intrinsic pathways that exist in SYNs to defend against viral infections, largely owing to the lack of appropriate cell based systems to model the unique functional and morphological features of these specialized cells in vivo. We have shown previously that primary human SYNs isolated from full-term placentas constitutively release type III interferons (IFNs) to limit the replication of viruses, including Zika virus (ZIKV). In addition we have developed three dimensional in vitro cell-line based models of human SYNs and second trimester human explant models that recapitulate the high resistance of SYNs to ZIKV infection and their constitutive release of type III IFNs. Collectively, these models provide new platforms to dissect the mechanisms involved in the protection of the human placenta from viral infections at many stages of human gestation.