Rotaviruses are ubiquitously infecting children under the age of 5 in both industrialized and developing countries disregarding hygiene and civilization status, being responsible for more than half million deaths each year and heavy economic burden worldwide. This mature double-stranded RNA virus is a triple layered virion containing a transcriptionally active particle, which must be delivered across the host cell membrane and into the cytoplasm to initiate viral replication. Therefore, a thorough understanding of the molecular mechanisms that rotaviruses utilize for cell entry can lead to the development of effective vaccination and therapeutic approaches to combat rotavirus. Given the fact that some important challenges still remain for a worldwide vaccine application, developing effective chemotherapeutic would be an excellent alternative approach to the vaccine development. The rotavirus cell entry process is complicated and not well understood. VP4 is the outermost layer spike protein projecting outward from mature rotavirus virions; VP4 plays important roles in rotavirus cell attachment and penetration. Rotavirus infectivity is remarkably increased by trypsin cleavage in vivo, a process that cleaves the spike VP4 into functional domains VP8* and VP5*. The VP8* domain is involved in rotavirus-cell recognition by interacting with Sia-containing receptors on the host cell surface at early stages of rotavirus cell entry. As the initial step in rotavirus infection is the binding of the virus to the host cell surface, an investigation into VP8*-receptors interactions may pave the way for designing therapeutic and preventative strategies against rotavirus diarrhoea. The primary aim of my research is to functionally and structurally characterize the binding affinity and specificity of VP8* from distinct origins with various Sia-containing agents. Gangliosides, which contain one or more Sia in their structure, are widely distributed on the cell surface of all mammalian cells and are considered as initial receptors of rotavirus. At the current stage, structural analyses are limited to the structures of VP8* in complex with mono Sia derivatives as no structural information of VP8* with large Sia-containing glycoconjugates (such as gangliosides) is available to date. In summary, I have determined and analyzed the structures of VP8* in complex with different mono Sia derivatives to generate information for the development of the structure-based inhibitor design against rotavirus disease. Most importantly, I have determined the first crystallographic structure of VP8* in complex with a ganglioside, which may provide an important platform to study further the interactions of rotavirus with those naturally occurring receptors at an early stage of rotavirus cell entry and broaden the current understanding of the mechanism mediating rotavirus-cell interactions.