Periodontal disease is a chronic microbial infection that triggers inflammation-mediated loss of the periodontal ligament and alveolar bone that supports the teeth. Because of the increasing prevalence and associated comorbidities, there is a need for the development of new diagnostic tests that can detect the presence of active disease, predict future disease progression, and evaluate the response to periodontal therapy, thereby improving the clinical management of periodontal patients. The diagnosis of active phases of periodontal disease and the identification of patients at risk for active disease represent challenges for clinical investigators and practitioners. Advances in diagnostic research are moving toward methods whereby the periodontal risk can be identified and quantified by objective measures using biomarkers. Patients with periodontitis may have elevated circulating levels of specific inflammatory markers that can be correlated to the severity of the disease. Advances in the use of oral fluids as possible biological samples for objective measures of the current disease state, treatment monitoring, and prognostic indicators have boosted saliva- and other oral-based fluids to the forefront of technology. Gingival crevicular fluid (GCF) is an inflammatory exudate that can be collected at the gingival margin or within the gingival crevice. This article highlights recent advances in the use of biomarker-based disease diagnostics that focus on the identification of active periodontal disease from plaque biofilms, GCF, and saliva.