Vertebrate poxviruses encode numerous proteins with the ankyrin (ANK) repeat, protein–protein interaction motif but little is known about the role(s) of this large family of poxvirus proteins. We report here that the vast majority of poxvirus ANK repeat proteins share a general molecular architecture that includes a conserved amino acid motif at the carboxyl terminus. This motif is most like the F-box seen in a range of cellular proteins. From 80–100% of the ANK repeat proteins of any one poxvirus have an F-box-like domain and we observed only one poxvirus protein with an F-box-like domain but lacking ANK repeats. The proteins of only one genus of vertebrate poxviruses lack F-box-like domains and this genus does not encode ANK repeat proteins. Many F-box proteins are recognition subunits of ubiquitin ligase complexes in which the F-box binds to core elements of the complex and protein–protein interaction domains in the remainder of the protein bind the substrate protein. These observations suggest a general model of the function of the poxvirus ANK-F-box proteins. We propose that the F-box-like domains in these proteins interact with cellular ubiquitin ligase complexes and thereby direct the ubiquitination of proteins bound to the ANK repeats. The large number of different poxviral ANK-F-box proteins suggests a wide range of cellular proteins might be subjected to ubiquitin-mediated degradation, thereby modulating diverse cellular responses to viral infection.