Zika is an arboviral illness caused by infection with the Zika flavivirus (ZIKV). Transmission most commonly occurs during a feeding event involving an infected Aedes mosquito or vertical transmission between an infected mother and her fetus. Infection outcomes range from asymptomatic to devastating neurologic injuries in children infected in utero. The recognition of Congenital Zika Syndrome (CZS) prompted declaration of a World Health Organization Public Health Emergency of International Concern for ZIKV and a call to rapidly develop medical countermeasures such as vaccines and therapeutics. A flurry of research and development activity in industry, government, non-governmental organizations, and academia during the most recent Zika epidemic (2015–2016) stimulated development of a number of vaccine candidate prototypes, generation of pre-clinical data, and the conduct of early phase human trials. The safety and immunogenicity of different vaccine platforms were demonstrated, and mouse and non-human primate passive transfer studies hinted at the potential for clinical benefit in humans and defining an immune correlate of protection. A rapid decline in regional transmission, however, prevented the conduct of a clinical endpoint efficacy trial. The pathway to licensure of a Zika vaccine remains unclear. Zika virus (ZIKV) is yet another arbovirusArbovirus (mosquito-borne flavivirus) that is rapidly emerging on a global scale, on the heels of a chikungunya (mosquito-borne alphavirus) epidemic in the Americas that began in 2013. A ZIKV epidemic that began in Brazil in 2015 spread rapidly to more than 30 countries in the Americas and the Caribbean, infecting more than two million inhabitants. Fortunately, the epidemic in the Americas disappeared at the end of the 2015–2016 mosquito-borne virus transmission season and widespread transmission has not returned to date. The reason is unknown but is likely a constellation of ecological factors as seen with other Arbovirusarbovirus outbreaks. Nonetheless, the explosive nature of recent outbreaks and concerning links to Guillain–Barre´ syndrome and microcephaly are incompletely understood. Also unknown is the relative importance of sexual transmission of ZIKV and asymptomatic ZIKV infections to the overall burden of transmission. The limited understanding of ZIKV presents an enormous challenge for responses to this rapidly emerging threat to human health. This chapter reviews the existing literature on ZIKV and identifies knowledge gaps.