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<p>Abstract</p> <p>Genome comparisons are behind the powerful new annotation methods being developed to find all human genes, as well as genes from other genomes. Genomes are now frequently being studied in pairs to provide cross-comparison datasets. This 'Noah's Ark' approach often reveals unsuspected genes and may support the deletion of false-positive predictions. Joining mouse and human as the cross-comparison dataset for the first two mammals are: two <it>Drosophila species, D. melanogaster </it>and <it>D. pseudoobscura</it>; two sea squirts, <it>Ciona intestinalis </it>and <it>Ciona savignyi</it>; four yeast (<it>Saccharomyces</it>) species; two nematodes, <it>Caenorhabditis elegans </it>and <it>Caenorhabditis briggsae</it>; and two pufferfish (<it>Takefugu rubripes </it>and <it>Tetraodon nigroviridis</it>). Even genomes like yeast and <it>C. elegans</it>, which have been known for more than five years, are now being significantly improved. Methods developed for yeast or nematodes will now be applied to mouse and human, and soon to additional mammals such as rat and dog, to identify all the mammalian protein-coding genes. Current large disparities between human Unigene predictions (127,835 genes) and gene-scanning methods (45,000 genes) still need to be resolved. This will be the challenge during the next few years.</p>