In recent years, there are increasing numbers and scales of large outbreaks of hand, foot and mouth disease (HFMD) accompanied by severe neurological complications in the Asia-Pacific region. Currently, there is still lack of efficient vaccines and anti-viral reagents for prevention and/or treatment of infection by enterovirus 71 (EV71) and coxsackievinis A16 (CA16), the two major cause agents of HFMD. Identification of the specific cellular receptor(s) is crucial for further elucidation of the molecular basis for early stage of virus-host interaction and pathogenesis. In the past year, discovery of P-selectin glycoprotein ligand-1 (PSGL-1), scavenger receptor class B member 2 (SCARB2) and sialy-lated glycans as functional receptors of EV71 and/or CA16 infection was reported. Here, the relevant experimental results and speculate further investigations and their application in future are discussed.