The primary focus of this chapter is on providing an overview of how we use the tools of functional genomics to study virus infection, the interferon response, and the mechanisms by which viruses attenuate or evade this response to ensure successful replication. We provide examples of the types of analyses we perform, experimental design considerations, and the tools and techniques we use for data processing and mining. We have not attempted to provide detailed protocols for performing microarray or proteomics experiments because even individual components of such analyses, for example, techniques for the isolation and amplification of ribonucleic acid, could easily be the subject of an entire chapter. Rather, our goal is to show how data obtained from global gene expression and protein profiling can be used to gain new insights into virus-host interactions, with particular emphasis on the interferon response and its modulation by virus infection.