Originally, comparative genomics was geared toward defining the synteny of genes between species. As the human genome project accelerated, there was an increase in the number of tools and means to make comparisons culminating in having the genomic sequence for a large number of organisms spanning the evolutionary tree. With this level of resolution and a long history of comparative biology and comparative genetics, it is now possible to use comparative genomics to build or select better animal models and to facilitate gene discovery. Comparative genomics takes advantage of the functional genetic information from other organisms, (vertebrates and invertebrates), to apply it to the study of human physiology and disease. It allows for the identification of genes and regulatory regions, and for acquiring knowledge about gene function. In this chapter, the current state of comparative genomics and the available tools are discussed in the context of developing animal model systems that reflect the clinical picture.