This manuscript reviews the development over the last 20 years of the evidence supporting the clinical application of a controlled delivery device for the treatment of human periodontitis. The device is a monolithic ethylene vinyl-acetate fibre loaded with 25% w/w tetracycline HCl (tetracycline fibre). It releases tetracycline at a steady state rate of 2 µg/cm · h and results in the maintenance of essentially constant, highly-effective concentrations of tetracycline at the site of action. A series of controlled, randomised, single-blind, phase-III clinical trials including a total of 463 patients has indicated that: (1) tetracycline fibres result in significantly better outcomes than the scaling and root planing positive control; (2) combination of tetracycline fibres with subgingival mechanical debridement results in significant improvement over debridement alone. Evidence from these studies has led to approval of this treatment modality by the US Food and Drug Administration and by the European Union Regulatory Bodies. A clinical usage study involving 2711 subjects treated by 68 clinicians in Europe and North America indicated that the magnitude of the observed clinical outcomes is clinically relevant and that adverse events were rarely observed. A variety of clinical investigations aimed at the optimal incorporation of tetracycline fibres in a treatment strategy provide guidance in case selection. Cost of therapy and concerns of unnecessary usage of antibiotics should be considered. It is nonetheless concluded that combination of tetracycline fibres with mechanical debridement represents a documented treatment alternative, the application of which may offer clinical benefits to many patients.