Zika virus (ZIKV) is an emergent arbovirus that has attracted attention in the last year as a possible causative agent of congenital malformation; it shows a remarkably increased microcephaly risk during otherwise healthy pregnancies. We present here an analysis of all ZIKV sequences available in Genbank up to April 2016, studying the mutations in the whole polyprotein and their possible structural implications for the proteins E, NS1, NS3 and NS5. This study suggests that microcephaly is not a consequence of any particular amino acid substitution but, conceivably, is a feature of ZIKV itself. Moreover, the structural analysis of ZIKV proteins, together with the mutational landscape of ZIKV and a structure-sequence comparison with other flaviviruses, allows the suggestion of regions that could be exploited as anti-ZIKV targets, including some allosteric sites found in the NS3 and NS5 proteins of DENV.