Enterovirus 71 (EV71) and Coxasackievirus A16 (CVA16), belonging to the Picornaviridae family, are the main causative agents of hand-foot-and-mouth disease (HFMD). Each year, more than a million incidences of HFMD are reported globally with periodic outbreaks of epidemics. Lack of effective therapeutics against the virus has increased public health concerns. A thorough understanding of the process of viral entry into host cells could help prioritize strategies to block this vital step in the life cycle of the virus. In context with this, several years of our efforts on studying picornaviruses have increased our understanding of the process of attachment and uncoating of the virus during infection. In particular, atomic structures of the ‘uncoating intermediate’ particle of CVA16, and mature, empty particles of EV71 and CVA16 (Wang et al., NSMB, 2012; Ren et al., Nat Comm., 2013) shed light on key structural changes accompanying viral morphogenesis during infection. These structures also provide detailed information about viral epitopes and are instructive for design of HFMD vaccines. Further, our studies on virus-receptor interactions under neutral and acidic conditions reveal an intriguing pH-induced conformational change in the receptor that leads to dislodgment of a natural lipid termed ‘pocket-factor’ from viral capsids. Removal of the pocket factor sets into motion a series of conformational changes of viral capsid, culminating in uncoating and release of viral RNA into host cell. Using the structures as guide, we have developed potent anti-HFMD virus inhibitors with picomolar EC50 values (De Colibus et al., NSMB, 2014). Employing novel methods, our studies scale new frontiers in virus-host receptor field. As such the work not only represents a landmark in the understanding of receptor-mediated entry of non-enveloped viruses into host cell, but also paves the way for development of potent therapeutics and vaccines to combat HFMD.