The emergence and subsequent global spread of SARS exposed the lack of basic understanding of factors that mediate coronavirus emergence and host range expansion.  Using the related coronavirus mouse hepatitis virus (MHV) as a model, a mechanism of host range expansion in which the virus evolves from a receptor specialist into a receptor generalist in response to environmental pressures has emerged.  In cell culture models of persistent infection in a single cell type and mixed infection in a mixed host cell environment, host range mutants with relaxed receptor specificity were generated. These mutant viruses are capable of recognizing orthologous and perhaps new receptors on cells of many species typically refractory to MHV infection.  The implications of this shift in receptor usage and its parallels in other viral systems suggest that the recognition of receptor orthologs and paralogs may be a common mechanism of RNA virus cross-species transmission and emergence of new human pathogens.