Comparative genomics approaches and multi-organismal biology are valuable tools for genetic analysis. Cross-species connections between genes mutated in human disease states and homologues in model organisms can be particularly powerful, as model-organism gene function data and experimental approaches can shed light on the molecular mechanisms defective in the disease. We describe a project that is systematically identifying novel expressed sequence tag (EST) sequences that are highly related to genes in model organisms and mapping them to positions on the mouse and human maps. This process effectively cross-references model organism genes with mapped mammalian phenotypes, facilitating the identification of genes mutated in human disease states via the positional candidate approach. A public database, XREFdb (http://www.ncbi.nlm.nih.gov/ XREFdb/), disseminates similarity search, mapping and mammalian phenotype information and increases the rate at which these cross-species connections are established.