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The reverse genetic system for the mouse hepatitis virus (MHV) in combination with a murine model for coronavirus infection allows for the use of genetically modified virus and host strains to assess the full range of virus-host interactions and to determine their impact on coronavirus pathogenicity. Reverse genetics facilitate the identification of replicase gene-encoded pathogenicity factors and the analysis of their impact on important aspects of virus-host interactions, such as virus sensing, induction of innate immune responses and mechanism of virus-induced immunopathology. The analysis of viral domains that are widely conserved within RNA viruses will furthermore allow the delineation of fundamental concepts of viral replication and pathogenicity.