Researchers involved in the delivery of periodontal therapy are currently investigating the possible use of oral fluids in the diagnosis of oral diseases and drug development. Substantial improvements have been made in the understanding of the mediators implicated on the initiation, pathogenesis, and progression of periodontitis. This review will analyze the mechanisms involved in the breakdown of periodontal supporting tissues during chronic periodontitis and highlights the potential array of biomarkers present in gingival crevicular fluid (GCF), which may relate to existing or predicted tissue regions undergoing metabolic change.