Mammalian reoviruses (MRV) are non-transforming RNA viruses that infect and kill transformed cells but remain relatively benign to normal cells. Yet, within the last half century, persistent infection (PI) of a growing variety of cells by wild type (wt) MRV has been reported. Classically studied L929 cells generally show extensive cytopathic effect (CPE) and lyse after infection with wt MRV. However, L929 PI can be established by infecting with either high-passaged defective MRV, low multiplicity of infection (MOI) wt MRV or high MOI wt virus in the presence of NH₄Cl. Most MRV PIs involve an initial period of host cell death, but the cell population then recoups to maintain a stable PI with either minimal background CPE, periodic outbursts of CPE or in some cases without further CPE. The dynamics of MRV replication during PI vary. Normal early peaks in viral replication are often reduced as PI is established and progresses, but in some cases near-peak replication is maintained. Interferons have been implicated in decreased MRV replication during PI in various cell-specific models, but the findings are not universal. PI has been reported in normal mammalian cells and more often in transformed mammalian cells but, paradoxical evidence suggests cellular transformation enhances host permissiveness to MRV replication and induces lysis. This requires that cell lines permissive to PI be programmed such that MRV are able to replicate while either signaling pathways related to MRV-induced host death are abrogated, or alternatively host survival pathways are activated allowing MRV-host symbiosis. Since PI negates host cell death, delineating the mechanisms which enable MRV PI could permit new methods for enhancing MRV’s potent potential as an oncolytic agent through exploitation of deduced MRV-induced host cell death pathways or manipulation of host survival pathways.