Although total joint replacement surgery is one of the most successful clinical procedures performed today, bone loss around knee and hip implants (osteolysis), resulting in aseptic loosening of the prosthesis, remains a major problem for many patients. Over the last decade much has been learned about this process, which is caused by wear debris particles that simulate a local inflammatory response and osteoclastic bone resorption. Aseptic loosening cannot be prevented or treated by existing nonsurgical methods. Gene transfer, however, offers novel possibilities. Here, we review the current state of the field and the experimental gene therapy approaches that have been investigated toward a solution to aseptic loosening of prosthetic implants.