Annotators of the human genome are increasingly exploiting comparisons with genomes at both the distal and proximal evolutionary edges of the vertebrate tree. Despite the sequence similarity between primates, comparisons among members of this clade are beginning to identify primate- as well as human-specific functional elements. At the distal evolutionary extreme, comparing the human genome to that of non-mammal vertebrates such as fish has proved to be a powerful filter to prioritize sequences that most probably have significant functional activity in all vertebrates.