Hand, foot and mouth disease (HFMD) is an acute viral illness that primarily affects infants and young children, and often occurs in clusters or outbreaks. The major causative agents of HFMD are coxsackievirus A 16 (CVAI6), human enterovirus 71 (HEV71) and coxsack-ievirus AIO (CVA10), of the genus Enterovirus in the family Picoaviridae. HFMD caused by EV71 is associated with severe neurological complications and death. Since the late 1990s, several major epidemics of EV71 HFMD have swept through the Asia-Pacific region, associated with a rapid fulminant course, severe neurolo-gical complications, and a large number of fatalities. Until now, little has been known about the genetics and transmission trends of the fast-mutation virus, and there is no effective and specific antiviral therapy or vaccine for HFMD. It is time to step up efforts to understand the molecular epidemics and pathogenesis so that we can develop effective management strategies and surveillance programs.