Human enterovirus 71 (HEV71) has been considered as an essential human pathogen, which causes hand, foot and mouth disease in young children. Several HEV71 outbreaks have been observed in many Asia-Pacific countries for the past two decades with significant fatalities. However, there are no competent vaccines or antivirals against HEV71 infection to date. Thus, it is of critical priority to delve into the search for anti-HEV71 agents. Prior to this, there is a need to gain knowledge about the distinct targets of HEV71 that are available and that have been exploited for antiviral therapy. This review aims to provide a better understanding of HEV71 virology and feature potential antivirals for progressive clinical development with respect to their elucidated mechanistic actions.