Total joint arthroplasty has revolutionized the treatment of arthritic and degenerative conditions for many joints in the body; however, wear debris is continuously generated with day-to-day use of an artificial joint. Excessive production of wear by-products induces a foreign body and chronic inflammatory reaction that accelerates periprosthetic bone destruction and inhibits bone formation. The specific biologic reaction is dependent on the type, amount, and characteristics of the by-products of wear, along with individual genetic variations. For polymeric and ceramic particles, the inflammatory reaction is generally nonspecific and nonimmune; however, with metallic by-products, a type IV, T lymphocyte-mediated, antigen-dependent immune reaction can occur in some patients. The production of proinflammatory cytokines, chemokines, reactive oxygen species, and other mediators is upregulated by wear particles. Animal models have shown that the biologic reaction to wear particles is systemic in nature, not a localized event. Mechanical stimuli and the presence of endotoxin also appear to be important. Efficacious biologic treatments of periprosthetic osteolysis are not yet available. Research continues with the hope that viable strategies for preventing and treating particle-induced osteolysis will be introduced in the future, thus mitigating the need for revision surgery.