An EV71 vaccine is now in stage 3 clinical trials and has proven safe and efficacious for Ev71 prevention. However, there is no evidence that it will provide immunity to other EVs such as CV-A16 and 6(26). Our research shows that there are many other non-Ev71 HFMD-causing EVs that should not be disregarded. Infections caused by more recently detected serotypes such as CV-A6 are not only on the rise but can be associated with severe symptoms. Therefore, even if the EV71 vaccine is highly effective, the number and severity of HFMD cases may not decrease significantly.