<p>Periodontitis (PD) is a complex inflammatory condition driven by the interplay of microbial, genetic, epigenetic, and environmental factors. While bacterial biofilms are regarded as the primary cause, growing evidence underscores the significant role of genetic predisposition in determining susceptibility to the disease, its progression, and treatment outcomes. This review explores the genetic polymorphisms of PD, focusing on genes related to inflammatory mediators, immune responses, antimicrobial peptides, matrix metalloproteinases, and vitamin D receptor pathways. Key epigenetic mechanisms including DNA methylation, histone modifications, non-coding RNAs, and emerging RNA methylation pathways are explored in their roles in modulating inflammation, tissue destruction, bone metabolism, and interactions between the host and microbes. Advances in transcriptomic technologies, particularly RNA sequencing, have enhanced our ability to identify molecular biomarkers and cell-specific gene expression profiles associated with disease severity and responses to treatment. The potential for leveraging genetic and epigenetic profiling presents an exciting avenue for personalized periodontal care, including the use of epigenetic therapies targeting pathways involved in inflammation and tissue regeneration. Nonetheless, the current body of evidence has limitations. These include significant variability across studies, inconsistent disease classification systems, small sample sizes, and a predominance of preclinical or exploratory research. Many biomarkers and therapeutic targets proposed to date require further validation before they can be routinely applied in clinical practice. While integrating genetic, epigenetic, transcriptomic, and clinical data holds promise for advancing precision periodontology, rigorous large-scale, and multicenter studies are essential to confirm clinical applicability, validate biomarkers, and facilitate their incorporation into evidence-based treatment protocols.</p>