Mammalian orthoreoviruses (reoviruses) serve as a tractable model system for studies of viral pathogenesis. Reoviruses infect virtually all mammals, but cause disease only in the very young. Prototype strains of the three reovirus serotypes differ in pathogenesis following infection of newborn mice. Reoviruses are nonenveloped, icosahedral particles that consist of ten segments of double-stranded RNA encapsidated within two protein shells, the inner core and outer capsid. High-resolution structures of individual components of the reovirus outer capsid and a single viral receptor have been solved and provide insight into the functions of these molecules in viral attachment, entry, and pathogenesis. Attachment of reovirus to target cells is mediated by the reovirus sigma1 protein, a filamentous trimer that projects from the outer capsid. Junctional adhesion molecule-A is a serotype-independent receptor for reovirus, and sialic acid is a coreceptor for serotype 3 strains. After binding to receptors on the cell surface, reovirus is internalized via receptor-mediated endocytosis. Internalization is followed by stepwise disassembly of the viral outer capsid in the endocytic compartment. Uncoating events, which require acidic pH and endocytic proteases, lead to removal of major outer-capsid protein sigma3, resulting in exposure of membrane-penetration mediator micro1 and a conformational change in attachment protein sigma1. After penetration of endosomes by uncoated particles, the transcriptionally active viral core is released into the cytoplasm, where replication proceeds. Despite major advances in defining reovirus attachment and entry mechanisms, many questions remain. Ongoing research is aimed at understanding serotype-dependent differences in reovirus tropism, viral cell-entry pathways, the individual and corporate roles of acidic pH and proteases in viral entry, and micro1 function in membrane penetration.