In many instances, the encounter between host and microbial cells can be, through a longstanding evolutionary association, 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 only ensue 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 in 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 a number of important general considerations required to maximize the significance of microarray analysis in order to faithfully depict relevant host-microbe interactions. Several advantages and limitations of microarray analysis that may directly impact the significance of array data are highlighted and discussed. Further, this review revisits and contextualizes recent transcriptional profiles that were originally generated to specifically study intricate cellular interactions between gingival cells and four important plaque microorganisms. This is, to our knowledge, the first report that systematically investigates the cellular responses of a cell line to challenge by 4 different microorganisms. 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 of the complex and dynamic interaction between the oral microflora and its host, which may lead, in the long run, to the development of novel, rational and practical therapeutic, prophylactic and diagnostic applications.