Loosening of joint replacement components is often multifactorial. The quality of initial fixation is very important to the outcome of the arthroplasty and is often a factor in short-term and long-term failure. This paper discusses another important factor of implant loosening, namely wear debris induced osteolysis. Macrophages activated by the phagocytosis of particulate wear debris are the key cells in this process, which can potentially occur in any implant system regardless of implant design or fixation mode. This is because each implant system creates wear debris from the articulating surfaces and the interfaces. The clinical consequences of wear debris cover a broad spectrum from radiolucencies to massive osteolysis and implant failure. For this reason, the reduction of wear debris should be a primary goal of orthopedic research in the future.