Osteolysis remains a common mode of total hip arthroplasty failure. In vitro and animal models have been used to determine the pathophysiology of osteolysis by carefully dissecting the biochemical pathways leading to particulate wear debris and periprosthetic bone loss. Numerous cytokines and inflammatory mediators, including TNF-α and IL-1, are critical participants in this cascade and may represent prime targets for pharmacologic intervention. Osteoclasts, the end effector cells involved in the osteolytic process, also represent potential targets. Cell surface receptors on osteoclast precursors, such as receptor activator of NF-κB (RANK) (on osteoclasts) and RANK-ligand (RANKL) (on stromal cells), provide opportunities to arrest osteoclast maturation. Enhancing the naturally occurring osteoprotegerin is another recent attempt at modulating osteoclast behavior and a possible target for pharmacologic therapies. Other nonoperative strategies include intercepting tumor necrosis factor-α activity, interfering with the RANK-RANKL interaction necessary for osteoclast development and maturation, bisphosphonate therapy, and using viral vectors to deliver genes. Although each of these approaches has potential benefits, there are substantial challenges to effective implementation. Until there is convincing evidence of efficacy in human clinical trials, we recommend vigilant screening and appropriate surgery with component loosening or substantial likelihood of loosening, periprosthetic fracture, or major bone loss.