Clinical signs and symptoms, as well as medical and dental history, are all considered in the clinical determination of gingival inflammation and periodontal disease severity. However, the "biologic systems model" highlights that the clinical presentation of periodontal disease is closely tied to the underlying biologic phenotype. We propose that the determination and integration of subject-level factors, microbial composition, systemic immune response, and gingival tissue inflammatory mediator responses will better reflect the biology of the biofilm-gingival interface in a specific patient and may provide insights on clinical management. Disease classifications and multivariable models further refine the biologic basis for the increasing severity of periodontal disease expression. As such, new classifications may better identify disease-susceptible and treatment-non-responsive individuals than current classifications that are heavily influenced by probing and attachment level measurements alone. New data also suggest that the clinical characteristics of some complex diseases, such as periodontal disease, are influenced by the genetic and epigenetic contributions to clinical phenotype. Although the genetic basis for periodontal disease is considered imperative for setting an inflammatory capacity for an individual and, thus, a threshold for severity, there is evidence to suggest an epigenetic component is involved as well. Many factors long associated with periodontitis, including bacterial accumulations, smoking, and diabetes, are known to produce strong epigenetic changes in tissue behavior. We propose that we are now able to rethink periodontal disease in terms of a biologic systems model that may help to establish more homogeneous diagnostic categories and can provide insight into the expected response to treatment.