Enterovirus outbreaks are endemic all over the world. The change of some species of Enterovirus from benign to pathogenic is still not fully understood, with so-called 'virulence determinants' thought to be evolutionarily acquired mutations that change the viruses' ability and specificity of infectivity. Mutations that affect viral ability to infect different cells may be selected by factors including the rate of entry into a cell or the ability to withstand harsh extra-cellular environments. Understanding the molecular mechanisms of infection is required for cell infection has the potential to design therapeutics and vaccines against these pathogens. This study examines Enterovirus A71, normally the cause of Hand, Foot, and Mouth Disease but more recently more severe diseases such as encephalitis and acute flaccid paralysis, through the lens of evolutionary selection, molecular mechanisms, and animal models.