Neutrophils play a major role in the host response against invading periodontopathogenic microorganisms. Localized aggressive periodontitis (LAgP) is associated with various functional abnormalities of neutrophils. Based on the recent findings, LAgP neutrophils are not "hypofunctional" or "deficient." They are "hyperfunctional," and their amplified activity is responsible for the tissue destruction in periodontal disease. Several signal transduction abnormalities are associated with elevated neutrophil function in LAgP. There is a strong correlation between defective chemotaxis and decreased intracellular Ca2+ levels; total calcium-dependent protein Kinase C (PKC) activity of neutrophils is significantly lower than healthy subjects; and there is a marked increase in diacylglycerol (DAG) accompanied by a pronounced decrease in DAG kinase activity. In a separate set of experiments on the involvement of the inducible cyclooxygenase isoform (COX-2) and the role of novel lipid mediators in the pathogenesis of periodontal disease, crevicular fluid samples from LAgP patients were found to contain prostaglandin E2 (PGE2) and 5-LO-derived products, leukotriene B4 (LTB4), and the biosynthesis interaction product, lipoxin LXA4. Neutrophils from peripheral blood of LAgP patients, but not from healthy volunteers, also generated LXA4, suggesting that this immunomodulatory molecule may have a role in periodontal disease. Lipoxin generation and its relationship to PGE2 and LTB4 can be visualized as an important marker for the pathogenesis of periodontal disease. Thus, major advances in our understanding of the role of the neutrophil in host defense against periodontal organisms have been made through studies of LAgP. LAgP is used as an example of a severe periodontal disease that is related to abnormal neutrophil function. In this model, it appears that a hyperresponsiveness of the neutrophil, due to cell priming/predisposition, results in enhanced tissue damage.