It is now well established that the major long-term complication after total joint replacement (TJR) is aseptic loosening of the prosthetic components. This problem, although initially described in subjects with components secured in bone with methacrylate cement, has also been recognized in patients who have undergone TJR using noncementing techniques. The relative roles of so-called “mechanical” and “biological” factors in the pathogenesis of implant loosening have been extensively examined, and it is now generally accepted that this process is indeed multifactorial. Dissecting the individual roles and interplay of mechanical, biomaterial, and biological events in the pathogenesis of implant loosening is of critical importance in developing new strategies to reduce the incidence of this complication. This review will focus on the role of paniculate debris generated from prosthetic materials and its role in the pathogenesis of peri-implant osteolysis and implant loosening.