The periodontal diseases are infections caused by bacteria in oral biofilm, a gelatinous mat commonly called dental plaque, which is a complex microbial community that forms and adhere to tooth surfaces. Host immune-pathogen interaction in periodontal disease appears to be a complex process, which is regulated not only by the acquired immunity to deal with ever-growing and -invading microorganisms in periodontal pockets, but also by genetic and/or environmental factors. However, our understanding of the pathogenesis in human periodontal diseases is limited by the lack of specific and sensitive tools or models to study the complex microbial challenges and their interactions with the host's immune system. Recent advances in cellular and molecular biology research have demonstrated the importance of the acquired immune system in fighting the virulent periodontal pathogens and in protecting the host from developing further devastating conditions in periodontal infections. The use of genetic knockout and immunodeficient mouse strains has shown that the acquired immune response, in particular, CD4⁺ T-cells plays a pivotal role in controlling the ongoing infection, the immune/inflammatory responses, and the subsequent host's tissue destruction.