Objective To understand the cause for the differences between potentially mild Southeast Asian and the more pathogenic ZIKV in South America. Methods A comparative genomic analysis was performed to determine putative causations stemming from ZIKV. Results Phylogenetic analyses integrating geographical and time factors revealed that Southeast Asian ZIKV might not be the direct source of South American outbreaks as previously speculated. Amino acid residues unique to South American ZIKV isolates at the envelope, pr and NS1 proteins are listed and shown in the structural context. These unique residues on external viral proteins are not found in Southeast Asian ZIKV and could be responsible for the ongoing outbreak either via an intrinsic property of the virus or interactions with human immunity. Only a selected few primer/probe sets currently in clinical use were identified of being capable of detecting ZIKV strains worldwide. The envelope proteins of dengue virus (DENV) and ZIKV also showed a remarkable degree of similarity especially at the surface residues. Conclusions These findings may help explain the cross-reactivity of DENV antibodies to ZIKV. Thus, major caveats must be exercised in using existing diagnostic tools for ZIKV.