Abstract: Members of Orthopoxviridae (OPXV) include cowpox virus (CPXV), vaccinia virus(VACV) and monkeypox virus (MPXV), they are more important pathogens of animalborne diseases to human. This review focuses on the immunomodulatory molecules encoded by OPXV and their action pathways,more detailly introduced the different strategies with blockading of host interferon responses, inhibiting of host TNFinduced responses and inactivating of key immune components of the host defense responses. This will improve our acquaintance about the molecular mechanism of evading the host immune responses, host specificity of infection and pathogenesis for poxviruses.