Aim: This review aims to highlight the emerging role of toll-like receptors (TLRs) in pathogenesis of periodontitis and negative regulation of TLR signaling. Background: Periodontal disease is the common chronic bacterial infection of the supporting structures of the teeth characterized by the tissue destruction. Bacterial plaque stimulates the host inflammatory response. It is now known that the immune response utilizes a family of pattern-recognition receptors (PRRs) called TLR as a tool to trigger an inflammatory response to microbial invasion. The TLRs expressed by epithelial cells of gingiva are constantly stimulated which release cytokines and defensins required for maintenance of oral health. The chronic stimulation of TLRs may leas to the disruption of epithelial barrier and allows microorganisms to enter the underlying connective tissue. This further activates TLRs present on additional cells of the periodontium, i.e., resident and non-resident cells. These TLRs activation may cause host tissue destruction due to an overproduction of proinflammatory cytokines as well other biological mediators. Review results: The electronic databases PubMed, MEDLINE, Cochrane, Scopus and Google Scholar were searched for available data in the present review. A database search yielded a total of 94 articles out of 56 included based on the core data. The results and subsequent conclusions were extracted and reviewed. Conclusion: It may be concluded that TLR signaling is crucial for maintenance of periodontal health as well as initiation and progression of periodontal disease. In spite of this, there are still lacks of information regarding the functional polymorphisms of genes that are involved in the stimulation and regulation of lipopolysaccharide mediated inflammatory processes. Clinical significance: Overactive TLRs might pivot into chronic inflammation, and so targeting TLRs might therefore lead to remission from this chronic inflammation. Therefore, further investigations are necessary to expand our knowledge to understand and develop therapies for major pathologic conditions.