The analysis of poxvirus genomes is complex, in part, because of their size (130-360 kb) and the fact that gene content is variable; a common set of 49 genes has been found in all sequenced poxviruses and an additional 41 genes are also present in all sequenced orthopoxviruses. As a group, poxviruses have a very broad range of eukaryotic hosts (including mammals, birds, reptiles and insects) and many poxvirus genes are associated with blocking host anti-viral responses. One consequence of this is that many poxvirus genes are not essential for growth in tissue culture and that extensive passaging in vitro results in the accumulation of mutations, including deletions that result in loss of gene function. Here, we review various comparative analyses of the poxviruses including gene prediction, gene conservation and function, genome organization, and poxvirus taxonomy and evolution.