Technical Abstract: Genomic-based approaches are driving fundamental changes in our understanding of microbiology. Comparative analysis of microbial strain is providing new insights into pathogen evolution, virulence mechanisms, and host range specificity. Most importantly, gene discovery and genetic variations can now be used in genotyping analyses and the rational design of vaccines. New research strategies employing high-throughput gene expression analysis are providing novel platforms for more comprehensive understanding of host–pathogen interactions. In particular, functional genomics is rapidly revolutionising the analysis of whole genome responses of host and pathogens, which will ultimately lead to a better understanding of disease processes and the mechanisms through which pathogens evade host immunity; identification of the genetic basis of host–pathogen interactions; and discovery of novel vaccines, drugs, and biotherapeutics. Ultimately, we will be able to monitor the two way conversation between hosts and pathogens with the rapidly developing public database of the completely annotated genomic sequence datasets of many hosts and pathogens, the use of sequence-based high-throughput expression profiling technologies, and integrated bioinformatic tools to analyse and interpret genomic data. Through these multiple and combined approaches, we will obtain a complete picture of infectious diseases, microbial pathogenesis and protective host immune mechanisms using an integrated systems biology that will be crucial in developing a new generation of intervention strategies against pathogens infecting humans and animals. Microarray-based technologies for studying genome-wide transcriptional profiling hold exceptional promise for infectious diseases studies, since transcriptional control plays a key role in host–pathogen interactions. Rapidly advancing microarray technology platforms (expression profiling) will allow greater flexibility by providing this technology with increasing array element densities, better detection sensitivities, and more highly cost-efficient protocols. Future challenges for microarray researchers will include developing databases and algorithms to manage and analyse the vast genomic-scale datasets and extracting meaningful biological information from them. Vaccinogenomics, the integration of pathogen and host genomics in vaccine research, is likely to revolutionise the way scientists approach the challenges of discovering safe and effective vaccines. The availability of the genomics tools described in this review provides unprecedented opportunities for the rational design of highly effective veterinary vaccines. Identifying genes and genetic variances that control mechanisms of immune evasion, disease resistance, and vaccine responsiveness will in the future fundamentally change vaccine discovery research and enable vaccinologists to design vaccines to control and eradicate pathogens in targeted animal populations. For example, the use of chicken lines with defined genetic backgrounds in modern production systems provides unique opportunities for applying vaccinogenomic approaches to enable the development of vaccines that perform consistently under field conditions. Paradoxically, the heterogeneity found in outbred livestock populations may also present opportunities for vaccinogenomics by enabling marker-assisted selection of good responders to vaccination. Ultimately, genetic markers of protective immunity may one day lead to practical applications in selective breeding programs to significantly increase disease resistance in farmed livestock and poultry, thereby improving animal welfare and the safety of our food supply.