The World Health Organization recently declared the Zika Virus (ZKV) epidemic that began in Brazil in 2015 and rapidly spread to surrounding countries in the Americas and Caribbean an international public health emergency. The most concerning feature of this global epidemic, which is primarily being spread by the Aedes species of mosquitos, is its association with fetal brain damage in Brazilian infants, manifesting as microcephaly. The link between maternal ZKV infection and fetal brain damage has been strengthened by a number of cases in which ZKV has been identified in the amniotic fluid, placenta, and tissues of affected maternal/fetal pairs. Thus, it is a global priority to rapidly develop strategies for prevention of maternal infection, primarily a maternal ZKV vaccine that can protect women from ZKV infection and/or the associated fetal disease. Yet, the lack of understanding of the natural maternal immune responses to ZKV infection and how they relate to fetal outcome will impede vaccine development. As virus-specific antibodies are often critical for protection against virus acquisition and are passed to the fetus during late pregnancy, we hypothesize that the magnitude and potency of the maternal antibody response against ZKV is indirectly associated with the severity of congenital ZKV infection. Understanding the relationship between maternal antibody responses, in utero virus transmission, and fetal outcome is critical to defining the immunologic roadmap for a maternal ZKV vaccine.