Periodontal disease (gingivitis and periodontitis) is an inflam-matory process caused by the activity of pathogenic bacteria and their products on the gingival sulcus, with the consequent activation of the immune response. Saliva and crevicular fluid contain a wide variety of enzymes and antimicrobial factors that are in contact with the supragingival and subgingival region, in-cluding β-defensins (hBDs). hHBDs are non-glycosylated, cysteine-rich cationic peptides produced by epithelial cells with antimicrobial and immunoregulatory effects, thus contributing to maintaining homeostasis in periodontal tissues. The changes in the microbiota and the immune response from a healthy peri-odontium to gingivitis and, finally, to periodontitis are complex. Their sever-ity depends on a dynamic balance between bacteria associated with plaque, genetic and environmental factors. Recent advances have made it possible to understand the implication of hBDs in the detection, diagnosis, and therapy of periodontal disease and the relationship between periodontitis and other inflammatory conditions. This review aims to describe the effect of hBDs on the immune response and its use as a possible marker of the inflammatory activity of the periodontal disease.