Inflammatory osteolysis is a relatively frequent and incapacitating complication of rheumatoid arthritis and other inflammatory diseases, and is induced by accelerated osteoclast recruitment and activation in bone under the aegis of cytokines produced in the inflammatory environment. The success of antitumor necrosis factor-α and interleukin-1 therapy in correcting this condition highlights the central role of these cytokines in this process. Recent years have witnessed a revolution in understanding the molecular mechanism and pathogenesis of this family of diseases. It is now clear that p38 mitogen-activated protein kinase plays an essential role in the production of proinflammatory cytokines and cytokine-induced osteoclastogenesis, thus providing a potential therapeutic target for prevention of pathologic bone loss. © 2007 Lippincott Williams & Wilkins, Inc.