"An instructive example of our inability to predict pandemic emergence, or to precisely characterize pandemic viral genetic evolutionary pathways, is that of the 2009 swine influenza pandemic caused by the H1N1pdm virus. This virus appeared in an era of unprecedented human and animal influenza viral surveillance and the near real-time deposition of thousands of influenza virus genome sequences into public databases. The first recognized human cases caused by the 2009 pandemic H1N1pdm virus occurred in Mexico. However, multiple co-circulating genotypes of related swine influenza A viruses, resulting from multiple complex reassortments of various swine influenza A virus lineages (including those similar to the 1918 pandemic H1N1 virus from which the ancestral 2009 swine virus lineage had been derived in 1918), were identified not only in swine populations in central Mexico but also in Asia. Clearly, most, if not all, of the major pre-emergence genetic events of 2009 had happened at some time, and in some unknown place, that escaped detection. Even if the future pandemic virus had been identified in swine populations in the months and years before 2009, it would likely not have been recognized as a virus with pandemic potential. This is because viral phenotypic properties associated with human adaptation and transmissibility cannot yet be predicted from genetic sequences. The implications are sobering: Identifying pre-pandemic viruses by increased viral surveillance in mammals and birds may be difficult or impossible. There is reason to believe that every influenza virus pandemic and panzootic/epizootic event (the animal counterparts to pandemics and epidemics in humans) may be fundamentally different from every other. Although these pandemic (or panzootic/epizootic) viruses-to-be already exist in nature, or evolve and adapt in humans or other mammals, there is a growing realization that each seems to achieve its host switch success through different cooperative polygenic adaptive mutations that, in unique combination, are able to support pandemic or panzootic spread."