Protein modification by ubiquitin or ubiquitin-like polypeptides is important for the fate and functions of the majority of proteins in the eukaryotic cell and can be involved in regulation of various biological processes, including protein metabolism (degradation), protein transport to several cellular compartments, rearrangement of cytoskeleton, and transcription of cytoprotective genes. The accumulated experimental data suggest that the ankyrin-F-box-like and BTB-kelch-like proteins of orthopoxviruses, represented by the largest viral multigene families, interact with the cellular Cullin-1- and Cullin-3-containing ubiquitin-protein ligases, respectively. In addition, orthopoxviruses code for their own RING-domain-containing ubiquitin ligase. In this review, this author discusses the differences between variola (smallpox), monkeypox, cowpox, vaccinia, and ectromelia (mousepox) viruses in the organization of ankyrin-F-box and BTB-kelch protein families and their likely functions.