In periodontal diseases, bacteria trigger inflammatory host responses which, along with the direct destructive effects of the bacteria, cause most of the tissue destruction. Periodontal inflammatory responses are, by and large, immunologic, and our understanding of these reactions has been advanced by the explosion of knowledge in immunobiology, some of which is discussed in this review. Understanding the role of immune cells and their regulatory cell surface molecules such as the MHC, CD antigens, and receptors, as well as knowledge of effector systems set into motion such as phagocytes and cytotoxic T-cells, and the effector molecules such as antibodies, complement, and cytokines, have led to better understanding of the complex pathogenesis of periodontal disease. The role of mediators including the matrix metalloproteinases, proteoglycans, the kinins and anaphylatoxins, and low molecular weight mediators including products of arachidonic metabolism is beginning to be elucidated in periodontal disease. Important avenues of research for development of diagnostic tests based upon host response are apparent. For example, tissue products released during periodontal inflammation including the metalloproteinases, elastase, cytokines, prostaglandins, antibodies, and complement components may provide the basis for future diagnostic indicator tests. The recognition that the neutrophil/antibody/complement axis is critical for protection against periodontal bacteria and that abnormalities in this system often lead to increased periodontal susceptibility provide approaches for the development of diagnostic tests assessing risk. A group of factors which are negative regulators of inflammation including TGF-beta, gamma-interferon, and IL-1 receptor antagonist provide potential for assessment of periodontal disease in remission or in the healing phase. Finally, factors such as HLA associations and the molecular basis for neutrophil abnormalities may provide genetic markers for periodontal disease susceptibility. Diagnostic factors based upon host response measures offer great potential for predicting host susceptibility and will likely be used in combination with microbial diagnostics which identify specific infecting organisms.