Poxviruses encode a broad range of proteins that counteract the formidable attack of the immune response initiated in the host after infection, among which are proteins that mimic the extracellular binding domain of host cytokine receptors and are secreted from virus-infected cells. A soluble interferon-gamma receptor (IFN-gamma R) is produced early after infection and efficiently blocks the binding of IFN-gamma to cellular receptors, thus inhibiting both the anti-viral and immune functions of IFN-gamma. An IFN-gamma R is highly conserved among members of the poxvirus family, suggesting a major role in viral pathogenesis. The highly species-specific nature of the IFN system enables questions concerning the evolutionary relationship between poxviruses and their hosts to be addressed. The IFN-gamma R encoded by myxoma virus, a natural pathogen of rabbits, is specific for rabbit IFN-gamma. However, the IFN-gamma R encoded by orthopoxviruses (vaccinia, cowpox, camelpox, ectromelia) shows a novel, broad species specificity suggesting that these viruses have evolved in several species. The implications for the unknown origin and natural host(s) of vaccinia virus are discussed.