Matrix metalloproteinases (MMPs), produced by both infiltrating and resident cells of the periodontium, play a role in physiologic (e.g., tooth eruption) and pathologic (e.g., periodontitis) events. The evidence for the role of MMPs in periodontal destruction has accumulated over three and a half decades, and it is now recognized that an imbalance between activated MMPs and their endogenous inhibitors leads to pathologic breakdown of the extracellular matrix during periodontitis. This understanding has stimulated the search for a number of synthetic inhibitors that could be used as potential therapeutic agents. Tetracycline analogues, as proteinase inhibitors, are currently closer to being used clinically than any other agents in periodontal therapy. Other MMP inhibitors, such as Batimastat (British Bio-technology, Oxford, UK), are currently being tested clinically for inhibition of cancer metastasis and other diseases. Multiple mechanisms of MMP inhibition by tetracycline analogues have been proposed. The nonantimicrobial chemically modified tetracyclines are potent inhibitors of MMPs, preventing collagen breakdown and alveolar bone loss in animal models of periodontitis. In addition, nonantimicrobial low doses of the commercially available semisynthetic tetracycline doxycycline, have been used in human clinical trails to reduce MMP activity in the gingival crevicular fluid and gingival tissues, with a resultant reduction in pocket depth and attachment loss. Of particular interest, periodontal research on the nonantimicrobial properties of tetracycline has generated new therapeutic approaches to a variety of medical disorders characterized by excess MMP activity.