The dance between microbes and the immune system takes place in all biological systems, including the human body, but this interaction is especially complex in the primary gateway to the body: the oral cavity. Recent advances in technology have enabled deep sequencing and analysis of members and signals of these communities. In a healthy state, the oral microbiome is composed of commensals, and their genes and phenotypes may be selected by the immune system to survive in symbiosis. These highly regulated signals are modulated by a network of microbial and host metabolites. However, in a diseased state, host-microbial networks lead to dysbiosis and considerable burden to the host prior to systemic impact that extends beyond the oral compartment. Interestingly, we presented data demonstrating similarities between human and mice immune dysbiosis and discussed how this affects the host response to similar pathobionts. The host and microbial signatures of a number of disease states are currently being examined to identify potential correlations. How the oral microbiome interacts with inflammation and the immune system to cause disease remains an area of active research. In this review, we summarize recent advancements in understanding the role of oral microbiota in mediating inflammation and altering systemic health and disease. In line with these findings, it is possible that existing conditions may be resolved by targeting specific immune-microbial markers in a positive way.