Noroviruses are highly prevalent enteric RNA viruses. Human noroviruses (HuNoVs) cause significant morbidity, mortality, and economic losses worldwide. Infections also occur in other mammalian species, including mice. Despite the discovery of the first norovirus in 1972, the viral tropism has long remained an enigma. A long-held assumption was that these viruses infect intestinal epithelial cells. Recent data support a more complex cell tropism of epithelial and nonepithelial cell types.