The spectrum of disease is influenced by factors related to both the pathogen and the host, as well as the end points used in defining disease. In this article, the issue of disease resistance versus susceptibility will be examined in the framework that genetic manipulation of either the pathogen or the host immune response alters the balance from disease protection towards pathogenesis. The response of the host may trigger both a protective and a pathogenic immune response. The failure to mount a protective immune response predisposes the pathogen to persistence, which then becomes the target for immunopathology. This review will examine the factors involved both in virus-mediated pathogenesis and in disease protection in the Theiler's model of human multiple sclerosis. By manipulating the character of the virus pathogen and the specificity of the immune response, the entire spectrum of human demyelinating disease is reproduced.