Osteoclastic bone resorption is a prominent feature of periodontal disease. Bone resorption via osteoclasts and bone formation via osteoblasts are coupled, and their dysregulation is associated with numerous diseases of the skeletal system. Recent developments in the area of mediators of osteoclastic differentiation have expanded our knowledge of the process of resorption and set the stage for new diagnostic and therapeutic modalities to treat situations of localized bone loss as in periodontal disease. This review describes the current state of knowledge of osteoclast differentiation and activity, mediators, and biochemical markers of bone resorption and their use and potential use in clinical periodontics. Finally, therapeutic strategies based on knowledge gained in the treatment of metabolic bone diseases and in periodontal clinical trials are discussed, and the potential for future strategies is proposed relative to their biologic basis. The intent is to update the field of periodontics on the current state of pathophysiology of the osteoclastic lesion and outline diagnostic and therapeutic strategies with a rational basis in the underlying biology.