Abstract: The variola and vaccinia orthopoxviruses express key proteins that can inhibit the host innate immune response. For example, orthopoxviruses encode a family of evolutionarily conserved poxvirus proteins that inhibit signaling by the Toll-Like Receptor (TLR) family. Two of these poxvirus proteins have been identified as robust determinants of vaccinia virus virulence-N1L and A52R-which are both vaccinia virus proteins that inhibit TLR signaling. The TLRs mediate the innate immune recognition of pathogens. Once engaged by a bacterial or viral pathogen, the TLRs ultimately activate the NF-KB and MAPK signaling pathways and drive cytokine expression. Other TLRs eventually activate the interferon regulatory factor-3 (IRF3) signaling pathway and NF-KB to drive interferon production. These innate immune responses stimulate a vigorous adaptive immune response. This review explores the known and hypothesized mechanisms of action of the identified inhibitors of TLR signaling and contrasts their function with other poxviral inhibitors of innate immunity. Finally, potential functions for other incompletely characterized members of this growing gene family are discussed.