Zika virus (ZIKV) is a mosquito-borne virus of the flavivirus genus in the Flaviviridae family. Flaviviruses are single-stranded, positive-sense RNA viruses that have been responsible for numerous human epidemics. Notable flaviviruses include mosquito-borne viruses such as yellow fever virus (YFV), Dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV), as well as tick-borne viruses including Powassan virus (POWV) and tick-borne encephalitis virus (TBEV). Despite having been relatively obscure until the past decade, ZIKV has become a major global health concern, and is a topic of active research following multiple outbreaks across the globe. Here, we discuss ZIKV pathogenesis and the associated immunopathology, as well as advances in research, therapies, and vaccines developed using models of ZIKV pathogenesis.