Human non-polio EVs are an emerging human health threat and result in a high burden on healthcare. EVs are among the most common infections in mankind, with 10–15 million infections and at least 30,000–50,000 hospitalisations (mostly meningitis) per year in the United States. Over the last decade, several EV outbreaks have been reported in Europe, Asia, the US, and Australia causing thousands of cases of Central Nervous System (CNS) infections with increased child mortality. EVs use the faecal-oral route for entry but questions remain on the mechanism of entry in the gut, and the way the virus spreads to the CNS. This complicated pathogenesis is difficult to mimic in animal models and there is no antiviral treatment available. Understanding disease, as well as the availability of a better testing platform, are needed to develop accurate treatment strategies.