The orchestration of the inflammatory responses to both infection and tissue damage is arguably the key physiological function of NF-κB, and thus interference with the activation of NF-κB represents an exceptional strategy for a successful pathogen to exploit to counter multiple host innate defense processes through the targeting of a single host regulatory pathway. Because of their large genomes, which typically encode ~200 proteins, and their unusual independence from the host nuclear transcriptional machinery, poxviruses are especially well suited to manipulate the cytoplasmic activation of NF-κB. Indeed, poxviruses are known to encode multiple proteins that regulate the activation of NF-κB in a variety of different ways and these can be considered potential paradigms for the development of novel anti-inflammatory therapies and more effective vaccines. Given the renewed interest in the pathogenesis of orthopoxviruses like smallpox and monkeypox, we review the current understanding of how the various classes of poxviral immunomodulatory proteins target and manipulate the NF-κB pathway.