In many instances, the encounter between host and microbial cells, through a long-standing evolutionary association, can be a balanced interaction whereby both cell types co-exist and inflict a minimal degree of harm on each other. In the oral cavity, despite the presence of large numbers of diverse organisms, health is the most frequent status. Disease will ensue only when the host-microbe balance is disrupted on a cellular and molecular level. With the advent of microarrays, it is now possible to monitor the responses of host cells to bacterial challenge on a global scale. However, microarray data are known to be inherently noisy, which is caused in part by their great sensitivity. Hence, we will address several important general considerations required to maximize the significance of microarray analysis in depicting relevant host-microbe interactions faithfully. Several advantages and limitations of microarray analysis that may have a direct impact on the significance of array data are highlighted and discussed. Further, this review revisits and contextualizes recent transcriptional profiles that were originally generated for the specific study of intricate cellular interactions between gingival cells and 4 important plaque micro-organisms. To our knowledge, this is the first report that systematically investigates the cellular responses of a cell line to challenge by 4 different micro-organisms. Of particular relevance to the oral cavity, the model bacteria span the entire spectrum of documented pathogenic potential, from commensal to opportunistic to overtly pathogenic. These studies provide a molecular basis for the complex and dynamic interaction between the oral microflora and its host, which may lead, ultimately, to the development of novel, rational, and practical therapeutic, prophylactic, and diagnostic applications.