A major challenge in clinical periodontics is to find a reliable molecular marker of periodontal tissue destruction with high sensitivity, specificity and utility. The aim of this systematic review is to evaluate available literature on 'the utility of molecular markers of soft and hard periodontal tissue destruction'. Based on the focused question, 'What is the utility of molecular markers of soft and hard periodontal tissue destruction', an electronic and manual search was conducted for human studies presenting clinical data for the potential of molecular markers of tissue destruction in biofluids; gingival crevicular fluid (GCF), saliva, and serum. Papers fulfilling the inclusion criteria were selected. All relevant data from the selected papers were extracted and recorded in separate tables for molecules in GCF, saliva, and serum. Within the defined limits of the Problem/Population, Intervention, Comparison, Outcome, the present analysis reveals that (a) no single or combination of markers exists that can disclose periodontal tissue destruction adequately; (b) while the most fruitful source of biomarkers for periodontal destruction appears to be in molecules tightly related to bone and soft tissue destruction, this remains to be objectively demonstrated. Currently, clinical measurements are still the most reliable. © 2011 John Wiley & Sons A/S.