The availability of detailed genome sequence is providing a blueprint for new approaches to the design of experiments to interrogate Host/Microbe interactions. On the microbe side well annotated reference genomes can guide transcriptome and proteome analysis and facilitate high throughput mutagenesis and phenotyping experiments. Acquiring genome information from microbial populations facilitate transmission tracking, evolution studies and can help identify emerging trends such as the evolution of antibiotic resistance. Such approaches can also help define the microbial communities living in and on the host. The availability of draft genomes for vertebrate hosts including humans, mouse and zebrafish are helping, again in terms of transcriptome, proteome and RNAi-type inhibition studies. They are also facilitating high throughput mutagenesis and phenotyping programmes that can provide valuable data to the community as open access. As we sequence human populations we can use this data to identify loci under selection in different human populations and even investigate rare mutations with extreme phenotypes. Here, specific examples built around infection models will be used to illustrate the power of some of these approaches.