Theiler's virus is a picornavirus of mouse which causes an acute encephalomyelitis followed by a persistent infection of the white matter of the spinal cord with chronic inflammation and demyelination. This late disease is studied as a model for multiple sclerosis. Inbred strains of mice differ in their susceptibility to persistent infection and demyelination. Resistant strains clear the infection after the acute encephalomyelitis. This observation is the basis of genetic studies which we used as a thread for this review. The H-2D locus has a major effect on susceptibility. The H-2Db gene is involved in a fast and intense CTL response which confers resistance. The Tcrb locus is also implicated, although there is no proof that the susceptibility gene in this region codes for the T-cell receptor. A complete screen of the genome uncovered the role of the Ifng locus and led to the demonstration that IFN-gamma limits viral spread in the white matter. The roles of NK cells and B cells in limiting the infection are discussed. CD4+ T cells participate both in protection against the infection and in demyelination. Finally, the effect of non-immune factors in resistance is illustrated by mice with mutations in the MBP or PLP gene.