Genes have perpetually been experiencing birth and death during the process of comprehensively genomic evolution. After a systematical investigation of the evolutionary trajectories of Mx homologs across Chordata, we restored the exquisite history of Mx development. The current findings strongly suggested that Mx genes have been undergoing dramatic expansions and losses in long-term evolution. What should be noteworthy is loss of Mx copy in all observed avian and re-duplication in the majority of mammals. We next confirmed the evolutionary profiling of Mx conferred divergent antiviral activity to Influenza A Virus, where mammals including human and mouse were entitled with strong antiviral activity, whereas, Aves consisting chicken and duck were completely deprived of this capability, implying a lineage-specific selection driven by an ever-changed pathogen environment. Functional differentiation of Mx1 and Mx2 in human and mouse provide specific mechanism for anti- host specific pathogens. Finally, we partially revealed the putative genetic mechanisms by which chicken Mx barely presented anti-virus capability based on the systematic structure and pathway analysis, which may be partially explained by evolution strategies of key genes responsible for influenza A virus replication. Our findings highlight that the evolutionary dynamics of Mx genes across species in Chordata change the genetic systems and take responsibility of phenotypic evolution/diversity.