Despite the success of treating rheumatic disorders with biologic therapies, joint replacement surgery still remains the final treatment option in many cases. Approximately 1.5 million joint arthroplastic operations are performed annually worldwide. Implant failure due to massive bone loss and aseptic loosening of prostheses, however, is a major complication of joint replacement, which can lead to high socioeconomic burdens both for the individual patient and for health-care systems. To date, there is no approved drug therapy to prevent or inhibit periprosthetic osteolysis, and aseptic loosening of prostheses can only be overcome by surgical revision. Research during the past decade, however, has unravelled much of the pathogenesis of aseptic prosthesis loosening and preclinical studies have identified potential targets for pharmaceutical treatments. This article highlights the importance of a cooperative interaction between rheumatologists and orthopedic surgeons, and presents novel insights into the molecular mechanisms behind aseptic loosening of prostheses. In addition, we outline potential perspectives for the development of future therapeutic strategies for this devastating complication.