Periodontitis is a chronic inflammatory disease that affects the supporting structures of teeth. In the literature, the association between the pathogenicity of bacteria and environmental factors in this regard have been extensively examined. In the present study, we will shed light on the potential role that epigenetic change can play on different facets of its process, more particularly the modifications concerning the genes involved in inflammation, defense, and immune systems. Since the 1960s, the role of genetic variants in the onset and severity of periodontal disease has been widely demonstrated. These make some people more susceptible to developing it than others. It has been documented that the wide variation in its frequency for various racial and ethnic populations is due primarily to the complex interplay among genetic factors with those affecting the environment and the demography. In molecular biology, epigenetic modifications are defined as any change in the promoter for the CpG islands, in the structure of the histone protein, as well as post-translational regulation by microRNAs (miRNAs), being known to contribute to the alteration in gene expression for complex multifactorial diseases such as periodontitis. The key role of epigenetic modification is to understand the mechanism involved in the gene-environment interaction, and the development of periodontitis is now the subject of more and more studies that attempt to identify which factors are stimulating it, but also affect the reduced response to therapy.