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Zika virus (ZIKV) has challenged the assumed knowledge regarding the pathobiology of flaviviruses. Despite causing sporadic and mild disease in the 50 years since its discovery, Zika virus has now caused multiple outbreaks in dozens of countries worldwide. Moreover, the disease severity in recent outbreaks, with neurological disease in adult and devastating congenital malformations in fetuses, was not previously seen. One hypothesis is that the virus has acquired mutations that have increased its virulence. Indeed, mutations in other arboviruses, such as West Nile virus (WNV), chikungunya virus (CHIKV), and Venezuelan equine encephalitis virus (VEEV), have enhanced outbreaks. This possibility, as well as alternative hypotheses, are explored here. Highlights ZIKV was originally identified in Africa in the 1940s. Human infection was confirmed in the 1950s. ZIKV caused several severe world-wide outbreaks in the last decade, with millions of people at risk of infection. Hundreds of thousands are suspected to have been infected, with disease signs and symptoms ranging from subclinical to fever in adults. The highest burden of disease is in the unborn. Severe outbreaks have been associated with the Asian and American lineage viruses. The other African lineage viruses are virulent in immunocompromised mouse models, and it is unclear if there is a genetic component to the outbreaks associated only with Asian or American ZIKV viruses. Several mutations are observed in Asian/American lineage ZIKV and not in African lineage ZIKV. Published mutations in prM (S139N) and NS1 (A188V and T233A) have shown to increase virulence in mouse models. [ABSTRACT FROM AUTHOR]