Rotavirus (RV) is one of the major pathogens responsible for acute viral gastro-enteritis in children. The infection of RV is dependent upon the recognition of the host cell specific receptors and attachment. Thus, receptors are the important factors of infection. Recent studies have suggested that a genetic factor might play a role in the susceptibility of hosts to RV infection. Histo-blood group antigens have recently been discovered as receptors binding to RV, which are important for the study of evolution. Thus it will be also crucial for the pathogenesis and epidemiology and prevention and treatment for RV. In this article, we will review the correlation of the RV infection and histo-blood group antigens and further discuss the development of optimal vaccine.