The recent rise in zoonotic diseases caused by viruses that jump between animals and humans highlights the need for ongoing surveillance of viruses circulating in wildlife. One such virus, Mammalian orthoreovirus (MRV), affects a range of mammals, including humans, and is linked to gastrointestinal, respiratory, and neurological disorders. MRVs belong to the Reoviridae family, a group of nonenveloped double-stranded RNA viruses, some of which have shown a promise as oncolytic viruses, viruses that target and destroy cancer cells. This chapter provides an overview of MRV in minks, bats, pigs, and humans, including its structure, life cycle, pathogenicity, and prevention and control strategies. This review also discusses the emerging potential of reoviruses as oncolytic therapies. This chapter highlights concerns about the risk of MRV and similar viruses becoming zoonotic or reverse zoonotic (transmitted between humans and animals), underscoring the need for continued monitoring of these viruses in humans, animals, and the environment.