Mammalian reoviruses serve as important models for studies of viral replication and pathogenesis. These viruses have been isolated from many mammalian species, including humans, and cause disease primarily in the very young. Reoviruses induce apoptosis by a novel mechanism that requires engagement of cell-surface receptors, intracellular signal transduction, and activation of NF-kappaB. Reovirus binding to both cell-surface sialic acid and junctional adhesion molecule 1 is required for NF-kappaB activation and apoptosis. However, receptor binding alone is not sufficient to evoke these events. Viral disassembly acts in concert with receptor binding to induce NF-kappaB activation and apoptosis. Nuclear translocation of NF-kappaB is followed by activation of both extrinsic and intrinsic cell-death pathways. Importantly, potently apoptotic reovirus strains are highly virulent in newborn mice, suggesting that NF-kappaB-dependent apoptosis is essential for reovirus-induced disease.