The 2015-16 Zika virus (ZIKV) epidemic has posed unprecedented concern for maternal-infant health, mainly due to the substantial risk of microcephaly and other neurological birth abnormalities associated with congenital ZIKV syndrome (CZS). As licenced vaccines and effective antivirals are still unavailable, attention has been focused on post-delivery in vitro or translational in vivo studies to understand the impact of maternal ZIKV infection on placentation and neurodevelopmental consequences for the foetus. Here, we review clinical and translational studies highlighting ZIKV-induced maternal-foetal interface dysfunction, adding to our previous observations of experimental ZIKV vertical transmission to pregnant rhesus monkeys and newly published post-epidemic findings about the theme. This comparative review focuses on the mechanisms by which the virus has a cytopathic effect on trophoblasts and macrophages during placentation in humans, nonhuman primates, and rodent transgenic models, crosses the placental barrier, replicates, and establishes a persistent uteroplacental infection. When considering the mechanism of ZIKV-induced birth defects in humans and other susceptible hosts, it becomes apparent how the various stages of the ZIKV cycle in the host (both the parent and offspring) unfold. This understanding presents specific opportunities for pharmacological intervention and the development of preventative vaccines.