SummaryThe orf virus (ORFV) is a zoonotic, epitheliotropic, DNA parapoxvirus that infects principally sheep and goats. Exposure of animals to the virus or immunization by an ORFV preparation can accentuate the severity of disease, which has provoked an interest in the underlying cellular, virological, and molecular mechanisms. The identified ORFV virulence genes and the fact that the virus can repeatedly infect a host, owing to its evasive mechanisms, contribute to the development of potent immune modulators in various animal species. ORFV has been developed as a vaccine in veterinary medicine. The unique host immune‐evasion ability of ORFV has made it an important candidate for vaccine vectors and biological agents (as an oncolytic virus). Genetic modifications using ORFV to obtain safe and efficient preparations and mechanistic studies are improvements to the currently available methods for disease treatment.