There is no doubt that plaque bacteria are necessary to initiate disease and drive the chronic inflammatory response in the periodontal tissues. At the same time, there is strong evidence that destructive processes occurring as part of the host inflammatory response are responsible for the majority of the hard- and soft-tissue breakdown leading to the clinical signs of periodontitis. The characteristic clinical signs of chronic periodontitis occur mainly as a result of activation of host-derived immune and inflammatory defense mechanism. IL-1 and TNF induce expression of other mediators that amplify the inflammatory response, such as prostaglandins, and lead to production of lytic enzymes and stimulate the production of chemokines. Investigations on the soluble protein delivery of antagonists to IL-1 and TNF in animal models have shown promising results. Collectively, the clinical, radiographic, and biochemical findings of these experiments show that IL-1 and TNF-alpha antagonists block the progression of the inflammatory cell infiltrate towards the alveolar crest and the recruitment of osteoclasts, and prevent the periodontal lesions may destroy the soluble cytokine antagonists prior to their peak activity, which may necessitate more frequent administration of the active agents to the defects. Thus, gene transfer of TNF receptor antagonists and IL-1ra may offer a more efficient mode of delivery of disease controlling agents to the periodontal structures. Periodontal treatment through the ages has focused on the reduction of bacterial infection by mechanical removal of infectious agents (i.e., SRP). Attempts at elimination of infectious agents often do not represent a definitive therapy in periodontitis, necessitating the administration of more sophisticated biological treatment modalities. A thorough understanding of the host inflammatory response in periodontal pathogenesis presents the opportunity for exploiting new treatment strategies for periodontitis by means of host response modulation. The rationale behind this approach is to aid the host in its fight against infectious agents by supplementing the natural inherent defense mechanism or to modify its responses by changing the course of inflammatory systems. Therefore, pharmaceutical inhibition of host response pathways that mimic endogenous anti-inflammatory mechanisms may prove to be an effective strategy for treating periodontal diseases. This would require the development of polypharmaceutical approaches controlling all pathways associated with inflammation and tissue destruction. Current research has focused on the use of SDD as a treatment modality, and SDD is the only systemically used host modulatory drug approved by the United States Food and Drug Administration.