The large size and complexity of the human genome have limited the identifi
cation and functional characterization of components of the innate immune s
ystem that play a critical role in front-line defense against invading micr
oorganisms. However, advances in genome analysis (including the development
of comprehensive sets of informative genetic markers, improved physical ma
pping methods, and novel techniques for transcript identification) have red
uced the obstacles to discovery of novel host resistance genes. Study of th
e genomic organization and content of widely divergent vertebrate species h
as shown a remarkable degree of evolutionary conservation and enables meani
ngful cross-species comparison and analysis of newly discovered genes. Appl
ication of comparative genomics to host resistance will rapidly expand our
understanding of human immune defense by facilitating the translation of kn
owledge acquired through the study of model organisms. We review the ration
ale and resources for comparative genomic analysis and describe three examp
les of host resistance genes successfully identified by this approach.