The precise genetic and molecular determinants of viral virulence are poorly understood. Genetic studies with influenza and reovirus have indicated that virulence is multigenic. The high frequency of mutation of RNA viruses can complicate genetic analyses of virulence, resulting in phenotypes that are difficult to interpret. The ease with which the reoviruses reassert genome segments has made it possible to isolate reassortants from parental viruses causing different patterns of animal disease. It has thus been feasible to show that each of the three outer capsid proteins plays a major role in the pathogenesis of animal infection: the viral haemagglutinin determines the specificity of the immune response and cell and tissue tropism; the <latex>$\mu$</latex>l c protein plays a central role in determining yield at portals of entry as well as in differentiated tissues; the <latex>$\sigma$</latex>3 protein inhibits host macromolecular synthesis. Thus virulence is clearly multigenic, with each of the viral components playing distinct roles.