The mammalian reoviruses are a tractable experimental system for studies of viral replication and pathogenesis. Reovirus virions are nonenveloped, double-shelled particles containing a genome of 10 segments of doublestranded RNA (Nibert and Schiff, 2001). Reoviruses have been isolated from many mammalian species, including humans, but reovirus disease is limited to the very young (Tyler, 2001). The pathogenesis of reovirus infection has been studied using newborn mice, in which serotypespecific patterns of disease have been identified (Tyler, 2001). The best characterized of these models is reovirus pathogenesis in the murine central nervous system (CNS) (Fig. 1). After primary replication in the intestine, type 1 reovirus strains spread by hematogenous routes to the CNS where they infect ependymal cells, leading to nonlethal hydrocephalus (Weiner et al., 1977, 1980; Tyler et al., 1986). In contrast, type 3 reoviruses spread primarily by neural routes to the CNS and infect neurons, causing fatal encephalitis (Weiner et al., 1977, 1980; Tyler et al., 1986; Morrison et al., 1991). These distinct patterns of disease segregate genetically with the S1 gene (Weiner et al., 1977, 1980; Tyler et al., 1986), which encodes the viral attachment protein, 1 (Weiner et al., 1980; Lee et al., 1981). These findings have led to the hypothesis that selective recognition of cell-surface receptors by 1 is responsible for the serotype-specific expression of reovirus-induced disease. For this reason, considerable effort has been focused on studies of 1 structure, 1 receptors, and mechanisms by which 1– receptor interactions lead to cellular injury.