Abstract Zika virus (ZIKV) infection is currently an epidemic in the western hemisphere. It is a WHO-declared ?Public Health Emergency of International Concern? since February 2016 due to the association of ZIKV infection with microcephaly and other neurologic abnormalities in babies infected in utero and with Guillain-Barre syndrome in infected adults. An estimated four million ZIKV infections have occurred in the Americas in 2016 and over two billion people live in areas conducive to mosquito-borne transmission of ZIKV worldwide. To date, autochthonous ZIKV infection has been reported in over 40 countries in the western hemisphere including the US protectorate, Puerto Rico, and state of Florida. There is a clear need for accurate and practical methods of detecting ZIKV infection as well as for the development of therapeutic agents and vaccines to combat the associated disease. Detection of ZIKV infection is hampered, however, by the cross-reactivity of anti-ZIKV antibodies with other arboviruses present in the same areas including DENV and CHIKV and visa-versa. Specifically, neutralization- based serodiagnostic tests (notably plaque-reduction neutralization tests, PRNT) cannot cleanly distinguish between seropositivity to different members of this set of arboviruses, perhaps because antibodies directed at neutralizing epitopes tend to be cross-reactive. In this application we propose an innovative and comprehensive method for discovering targets of non-cross-reactive antibodies to emerging and established arboviruses and propose to begin with ZIKV due to the international public health emergency created by this virus.