Specific microorganisms initiate the immunoinflammatory processes that destroy tissue in periodontitis. Recent work has demonstrated, in addition to bacterial control, that modulation of the host immunoinflammatory response is also capable of controlling periodontitis. Matrix metalloproteinases (MMPs) destroy collagen and other matrix components, and the osteoclastic bone remodeling determines the periodontal bone response to a bacterial challenge. Other components of the biology, including cytokines and prostanoids, regulate MMPs and bone remodeling and are also involved in regulating the production of defensive elements, such as antibody. Agents directed at blocking MMPs or osteoclastic activity are effective in reducing periodontitis. Agents that inhibit prostaglandin E2 and selective blockage of specific cytokines have also been effective. Improved knowledge of bacterium-host interactions and of the processes leading to tissue destruction will help to identify targets for host modulation to reduce periodontitis in selected situations.