In recent years, our understanding of the role of natural killer (NK) cells in 
the response to viral infection has grown rapidly. Not only do we realize 
viruses have many immune-evasion strategies to escape NK cell responses, but 
that stimulation of NK cell subsets during an antiviral response occurs through 
receptors seemingly geared directly at viral products and that NK cells can 
provide a memory response to viral pathogens. Tremendous knowledge has been 
gained in this area through the study of herpes viruses, but appreciation for 
the significance of NK cells in the response to other types of viral infections 
is growing. The function of NK cells in defense against poxviruses has emerged 
over several decades beginning with the early seminal studies showing the role 
of NK cells and the NK gene complex in susceptibility of mouse strains to 
ectromelia, a poxvirus pathogen of mice. More recently, greater understanding 
has emerged of the molecular details of the response. Given that human diseases 
caused by poxviruses can be as lethal as smallpox or as benign as Molluscum 
contagiosum, and that vaccinia virus, the prototypic member of the pox family, 
persists as a mainstay of vaccine design and has potential as an oncolytic virus 
for tumor therapy, further research in this area remains important. This review 
focuses on recent advances in understanding the role of NK cells in the immune 
response to poxviruses, the receptors involved in activation of NK cells during 
poxvirus infection, and the viral evasion strategies poxviruses employ to avoid 
the NK response.