Zika virus has become a global health crisis, causing devastating effects on lives of almost five thousand pregnant women and their newborns. One of the often overlooked facts is that Zika virus has been in circulation in Southeast Asia for several decades without distinct manifestations of neurological pathologies. An understanding of the cause for discrepancy between potentially mild Southeast Asia and more aggressive Zika viruses in South America could reveal the mechanisms underlying outbreaks and neurological damages of Zika infections in Brazil. We performed a comparative genomic analysis was performed to determine putative causations stemming from the virus. Phylogenetic analyses integrating geographical and time factors showed that Asian Zika virus might not be the direct source of South American outbreaks as previously speculated. The differences in amino acid residues between Southeast Asian and Brazilian Zika viruses are specifically clustered on the outer surfaces of Envelope and NS1 proteins. Comparative genomic analyses also revealed that only a selected few primer/probe sets currently in clinical use are capable of detecting Zika virus strains worldwide. Interestingly, the Envelope proteins of Dengue and Zika viruses show a remarkable degree of similarity especially at the surface residues. This pattern explains the cross-reactivity of Dengue virus antibodies to Zika viruses. It also suggests that therapeutic antibodies and vaccine candidates against Dengue viruses can target the Zika virus, thereby providing a strategy for using already available means to treat and prevent Zika virus infection.