In recent times, loosening of joint prosthesis resulting in failure, is of grave concern to orthopedicians. It is estimated that 50% of total hip replacements become loose after 15 years, and most of them require either revision surgery or resection orthoplasty. Neither, newer operative techniques, change in design, use of novel materials, nor surface modifications have helped to circumvent the problem. It is in this context, that attention has been focussed on the role of tissue surrounding the implant, in the loosening of the prosthesis. Tissue response around prosthesis results in either formation of a fibrous layer around the implant, ingrowth into fenestrations on implant or direct bone apposition on prosthesis. Long-term implantation results in implant debris being released into surrounding tissue. These particles initiate a chronic granulonatous inflammation with a significant number of activated macrophages and foreign body type of giant cells, all engaged in attempts to get rid of the debris. These features have been found to be invariably associated with peri-prosthetic lysis of bone. Since such bone resorption is also observed around non-cemented prosthesis, possibly causes other than cement are responsible for the osteolysis. Retrospective studies on failed implants suggest that peri-prosthetic osteolysis is mediated by activated macrophages. Cytokines are capable of stimulating bone resorbing cells, the osteoclasts. Bone resorption results in further loosening of the prosthesis, changes in stress, frictional wear, release of more wear debris and recruitment of more macrophages. Bone death and proliferation of macrophages, thus appear to be the cause for pain and loosening of prosthesis.