In the last several years, the momentum towards utilizing global profiling methods has increased, and many studies have incorporated these approaches in order to gain insights into previously undetected host or microbe responses during the host-microbe encounter. Over 100 studies available on NIH Pubmed have used microarrays or similar technologies to assess the transcriptional basis for observed physiological outcomes. Further, these studies have revealed a high level of transcriptional activity that is not readily observable and, indeed, often phenotypically silent; presumably the cell’s attempt to maintain homeostasis and symbiotic harmony (12, 28). Additionally, proteomic studies which profile the entire arsenal of proteins present in a cell at a given time are now also possible. Each technique has its own advantages and limitations, and the technologies themselves are reviewed elsewhere (3, 10, 16, 19, 20, 30, 34). As also reviewed previously, the epithelium is the first line of defense to human infections initiating at mucosal membranes (4, 7), and several studies have demonstrated the specific and active nature of the epithelial response to microbial encounters. The response of the epithelium to bacterial, viral, fungal and protozoal challenge has yielded significant insights into the role of the epithelium in host defense. In addition to a passive role as a physical barrier, the epithelium actively participates in the recruitment of immune effectors, and can directly fend off microbes via defensins and other innate immune mechanisms. Despite the useful information that can be gained from transcriptional or proteomic approaches that study the epithelium, only a limited number of studies have been performed which are specifically targeted to the oral epithelium. Even fewer are targeted specifically to probe host-pathogen interactions of the oral epithelium, as many global genomic studies focus on oral carcinogenesis. Nonetheless, profiling of the host epithelium and/or the infecting microbe has emerged as a useful reporter of specific interactions. Both in vitro and in vivo studies have been performed which have yielded potential markers for periodontal disease progression, novel targets for therapeutics, and have improved the general understanding of host-pathogen cross talk. This review will highlight some important studies which have been conducted to gain insight into cellular and bacterial transcriptional and proteomic profiles associated with the oral cavity. In general, we will consider both sides of the story; the host perspective and that of the colonizing microbe. In closing, the state of the field will be considered and some suggestions will be made to best utilize existing data and overcome existing challenges to understanding the complex interplay between host and microbe in the oral cavity.