Aseptic loosening as a result of wear debris is considered to be the main cause of long-term implant failure in orthopaedic surgery and improved biomaterials for bearing surfaces decreases significantly the release of micrometric wear particles. Increasingly, in-depth knowledge of osteoimmunology highlights the role of nanoparticles and ions released from some of these new bearing couples, opening up a new era in the comprehension of aseptic loosening. Mouse models have been essential in the progress made in the early comprehension of pathophysiology and in testing new therapeutic agents for particle-induced osteolysis. However, despite this encouraging progress, there is still no valid clinical alternative to revision surgery. The present review provides an update of the most commonly used bearing couples, the current concepts regarding particle-cell interactions and the approaches used to study the biology of periprosthetic osteolysis. It also discusses the contribution and future challenges of mouse models for successful translation of the preclinical progress into clinical applications.