The dynamic interactions of the major respiratory microbial pathogens are complex. An understanding of the impact on naturally acquired immune responses to respiratory polymicrobial commensal bacteria is slowly evolving. Maintaining a micro-floral balance and the host's ability to respond to imbalances associated with disease is critical. Studies of acquired immune responses have found that both antibody and cellular immune responses are suppressed by the presence of multiple bacteria when compared with colonization by the single microbe. Microbes interact with the mucosal epithellum through a range of receptor-ligand interactions, including interactions with Toll-like receptors and adhesion molecules. Regulation of the inflammatory response associated with commensal colonization suggests a possible role for Treg cells in controlling the upper air way responses to bacterial microflora with both bacteria-bacteria and bacteria-host interactions affecting colonization and immune responses.