Recent findings demonstrate that human histo-blood group antigens (HBGAs) serve as receptors for norovirus infection. The recognition of human HBGAs by noroviruses is a typical protein-carbohydrate interaction, in which the protruding domain of the viral capsid protein forms an interface with the oligosaccharide side-chains of the antigens, with a wide diversity among different strains. The human HBGA system is also highly polymorphic and is controlled by multiple gene families with silent alleles. The presence of such diversified molecules on the cell surfaces indicates a possible host defense mechanism against the changing external environment. As mild pathogens that replicate possibly only in the intestinal tract, noroviruses have developed unique strategies to overcome the host defense system. This has been shown by their genetic and structural variations, which explains why norovirus-associated diseases are so common and widespread in every population worldwide.