Periprosthetic osteolysis is the most common long-term complication of a total joint arthroplasty, often resulting in aseptic loosening of the implant, which occurs in up to 34% of younger implant recipients and usually requires surgical revision. Particulate wear debris, continuously generated by articulating motion at the bearing surfaces, has been implicated as one of the primary causes of periprosthetic bone loss and implant loosening. With developing implants and bearing surfaces designs, various types of wear particles with specific chemical nature, dimension and shape are formed, which may initiate different immune or inflammatory responses. Wear debris induces down-regulation or up-regulation of various pro-inflammatory cytokines and chemokines in a range of cell types at the interface between implants and the surrounding bone, such as macrophages, osteoclast precursor cells, osteoblasts, lymphocytes, fibroblasts etc. Concomitantly, these mediators further affect functions of cells through distinct signaling mechanisms in either an autocrine or a paracrine manner. This review summarizes current concepts of how wear debris causes osteolysis, and describes the interaction and effects of wear debris on functions of primary cell types involved in osteolysis.