Operative joint replacement to treat disabling joint conditions secondary to degenerative and inflammatory arthritides has become one of the most efficacious and cost-effective procedures to relieve pain and restore joint function. However, prosthetic implants are not built to last forever and osteolysis and aseptic loosening has been associated with prosthetic arthroplasties since their introduction. The functional life of a synthetic joint is influenced by many factors including the material of the implant, operation procedures and the surgeon involved, as well as patient-related factors. Although promising developments have been achieved in this field, more than 10% of all implants still have to undergo operative revision within 15 years after the initial operation. Failure due to sepsis, fractures and dislocations has become rare; premature loosening of implants on the other hand is becoming much more important. Prosthetic loosening without concurrent infection or trauma is called aseptic loosening. It is generally accepted that small particles ("wear debris") and activated macrophages play a key role in aseptic loosening. The pathophysiology of this condition, however, is still not very well characterized. In this article, we review the molecular mechanisms and signal pathways that were unravelled as responsible factors for loosening orthopaedic implants. Finally, we discuss possible novel strategies for future therapeutic approaches.