The biologic effects of wear debris are an important factor limiting the longevity of total joint replacements. In vivo, in vitro, and tissue retrieval studies have underlined a central role for the macrophage in the etiology of loosening and periprosthetic osteolysis. Wear particles from the materials used for total joint replacement activate macrophages to secrete proinflammatory factors. Complex interactions between macrophages and other cells stimulate bone resorption and suppress bone formation at the prosthetic interface. To improve the long term outcome of joint replacements, future research must find innovative approaches to minimize the production and biologic effects of wear debris.